bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type checking modular multiple dispatch with parametric polymorphism and multiple inheritance
Authors: Allen Eric , Hilburn Justin , Kilpatrick Scott , Luchangco Victor , Ryu Sukyoung , Chase David , Steele Guy 
Published: December 2011

In previous work, we presented rules for defining overloaded functions that ensure type safety under symmetric multiple dispatch in an object-oriented language with multiple inheritance, and we showed how to check these rules without requiring the entire type hierarchy to be known, thus supporting modularity and extensibility. In this work, we extend these rules to a language that supports parametric polymorphism on both classes and functions.
In a multiple-inheritance language in which any type may be extended by types in other modules, some overloaded functions that might seem valid are correctly rejected by our rules. We explain how these functions can be permitted in a language that additionally supports an exclusion relation among types, allowing programmers to declare "nominal exclusions" and also implicitly imposing exclusion among different instances of each polymorphic type. We give rules for computing the exclusion relation, deriving many type exclusions from declared and implicit ones.
We also show how to check our rules for ensuring the safety of overloaded functions. In particular, we reduce the problem of handling parametric polymorphism to one of determining subtyping relationships among universal and existential types. Our system has been implemented as part of the open-source Fortress compiler.
Iterative data-parallel mark&sweep on a GPU
Authors: Veldema Ronald , Philippsen Michæl 
Published: December 2011

Automatic memory management makes programming easier. This is also true for general purpose GPU computing where currently no garbage collectors exist. In this paper we present a parallel mark-and-sweep collector to collect GPU memory on the GPU and tune its performance. Performance is increased by: (1) data-parallel marking and sweeping of regions of memory, (2) marking all elements of large arrays in parallel, (3) trading recursion over parallelism to match deeply linked data structures.
(1) is achieved by coarsely processing all potential objects in a region of memory in parallel. When during (1) a large array is detected, it is put aside and a parallel-for is later issued on the GPU to mark its elements. For a data-structure that is a large linked list, we dynamically switch to a marking version with less overhead by performing a few recursive steps sequentially (and multiple lists in parallel).
The collector achieves a speedup of a factor of up-to 11 over a sequential collector on the same GPU.
Integrated symbol table, engine and heap memory management in multi-engine prolog
Authors: Tarau Paul 
Published: December 2011

We describe an integrated solution to symbol, heap and logic engine memory management in a context where exchanges of arbitrary Prolog terms occur between multiple dynamically created engines, implemented in a new Java-based experimental Prolog system.
As our symbols represent not just Prolog atoms, but also handles to Java objects (including arbitrary size integers and decimals), everything is centered around a symbol garbage collection algorithm ensuring that external objects are shared and exchanged between logic engines efficiently.

Taking advantage of a
tag-on-data
heap representation of Prolog terms, our algorithm performs in-place updates of live symbol references directly on heap cells.

With appropriate fine tuning of collection policies our algorithm provides an integrated memory management solution for Prolog systems, with amortized cost dominated by normally occurring heap garbage collection costs.
The Evolution of Endothelial Regulatory Paradigms in Cancer Biology and Vascular Repair
Authors: Franses Joseph W. , Edelman Elazer R. 
Published: December 2011

Abstract
Although the roles of endothelial cells in cancer have primarily been considered to be related to tumor perfusion, the emerging appreciation of “angiocrine” regulation adds stromal regulatory capabilities to the expanding list of endothelial functions in tumors. We posit that an understanding of the state-dependent paracrine regulatory paradigms established in vascular disease and repair will be critical for a deep understanding of tumor biology, as endothelial cells regulate diverse processes in all vascularized tissues. Here, we outline the historical developments that led to the appreciation of the paracrine regulatory functions of endothelial cells, summarize classical views of blood vessels and stroma in cancer, and attempt to merge these ideas to include the stromal regulatory endothelial cell as a critical regulator of cancer. The notion of the endothelial cell as a biochemical regulator of cancer state in constant dynamic balance with its tumor could impact diagnosis, prognosis, and treatment of cancer. Such concepts might well explain the mixed results from antiangiogenic cancer therapeutics and how certain drugs that improve vascular health correlate with improved cancer prognosis. Cancer Res; 71(24); 7339–44. ©2011 AACR.
Tumor Infiltration by T Lymphocytes Expressing Chemokine Receptor 7 (CCR7) Is Predictive of Favorable Outcome in Patients with Advanced Colorectal Carcinoma
Authors: Correale Pierpaolo , Rotundo Maria Saveria , Botta Cirino , Del Vecchio Maria Teresa , Ginanneschi Chiara , Licchetta Antonella , Conca Raffaele , Apollinari Serena , De Luca Fabio , Tassone Pierfrancesco , Tagliaferri Pierosandro 
Published: December 2011

AbstractPurpose: An efficient adaptive immunity is critical for a longer survival in cancer. We investigated the prognostic value of tumor infiltration by CD8+ T cells expressing the chemokine-receptor-7 (Tccr7) and the correlation between tumor infiltration by Tccr7 and regulatory CD4+FoxP3+ T cells (Treg) in 76 metastatic colorectal cancer (mCRC) patients enrolled in a phase III trial.Experimental Design: Tccr7 and Treg cell infiltration in tumor samples was quantified by immunohistochemistry. The correlation among Tccr7, Treg tumor infiltration, and patients' outcome was evaluated.Results: High Tccr7 tumor infiltration was predictive of prolonged OS [high vs. low Tccr7 score: median 38 months (95% CI: 24.5–51.4) vs. 20 months (95% CI: 11.4–28.5); HR = 0.48 (95% CI: 0.24–0.96); P = 0.03] and prolonged progression-free survival [PFS; high vs. low Tccr7 score: median 12 months (95% CI: 7.7–16.2) vs. 7 months (95% CI: 5.2–8.7); HR = 0.54 (95% CI: 0.28–1.01); P = 0.01] after front-line chemotherapy. Regression analysis did not show correlation between Tccr7 and Treg infiltration levels. However, the cluster of patients showing concomitant high infiltration by both Tccr7 and Treg disclosed a favorable outcome [double high vs. double low tumor infiltration score: median OS = 35 months (95% CI: 20.8–49.1) vs. 17 months (95% CI: 4.6–29.3); HR = 0.32 (95% CI: 0.12–0.87); P = 0.02 and median PFS = 11 months (95% CI: 9.4–12.5) vs. 5 months (95% CI: 2.2–7.7); HR = 0.43 (95% CI: 0.17–1.06); P = 0.01].Conclusions: High Tccr7 tumor infiltration score is a favorable prognostic factor for mCRC. Our findings underline the relevance of microenvironment-related immunologic events for patient outcome. Clin Cancer Res; 18(3); 850–7. ©2011 AACR.
Targeting the mTOR/4E-BP Pathway in Endometrial Cancer
Authors: Korets Sharmilee Bansal , Czok Sarah , Blank Stephanie V. , Curtin John P. , Schneider Robert J. 
Published: December 2011

AbstractEndometrial cancer is the most common gynecologic malignancy. Although it is highly treatable in the early stages of disease, therapies for advanced and recurrent disease are rarely curative. A molecular and genetic understanding of endometrial cancer involves the mTOR signaling pathway, an emerging target for treatment of type I disease (the most common presentation). Endometrial cancers show a significant reliance on the mTOR pathway for survival, and studies to date have revealed a clinical advantage in targeting this pathway. Less well developed in the study of endometrial cancer is an understanding of mTOR signaling to its major downstream effector, translational control. Given the poor rate of success for treatment of late-stage endometrial cancer, increasing attention is being directed to the development of new therapeutic approaches, including targeting the mTOR pathway. Here, we discuss the potential benefit of targeting mTOR combined with existing chemotherapies by monitoring its impact on translational regulatory pathways and key translation targets in endometrial cancer. We also highlight laboratory and clinical research findings that will provide new avenues for future research and clinical development. Clin Cancer Res; 17(24); 7518–28. ©2011 AACR.
MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model
Authors: Bartholomeusz Chandra , Oishi Tetsuro , Saso Hitomi , Akar Ugur , Liu Ping , Kondo Kimie , Kazansky Anna , Krishnamurthy Savitri , Lee Jangsoon , Esteva Francisco J. , Kigawa Junzo , Ueno Naoto T. 
Published: December 2011

Abstract
Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is extracellular signal–related kinase (ERK). PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR–ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of 4 CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Furthermore, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to selumetinib sensitivity. Both selumetinib and erlotinib significantly suppressed tumor growth (P &lt; 0.0001) in a CCC xenograft model. However, selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss and severe skin peeling) at high doses. Our findings indicate that the MEK–ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that selumetinib and erlotinib are worth exploring as therapeutic agents for CCC. Mol Cancer Ther; 11(2); 360–9. ©2011 AACR.
Cancer Risks for the Relatives of Colorectal Cancer Cases with a Methylated MLH1 Promoter Region: Data from the Colorectal Cancer Family Registry
Authors: Levine A. Joan , Win Aung Ko , Buchanan Daniel D. , Jenkins Mark A. , Baron John A. , Young Joanne P. , Long Tiffany I. , Weisenberger Daniel J. , Laird Peter W. , McCall Rebecca L. , Duggan David J. , Haile Robert W. 
Published: December 2011

Abstract
Methylation of the MLH1 gene promoter region is an underlying cause of colorectal cancer (CRC) with high microsatellite instability (MSI-H) diagnosed in persons without a germ line mutation in a mismatch repair (MMR) gene (non–Lynch Syndrome CRC). It is unclear whether relatives of CRC cases with MLH1 methylation have an increased risk of colorectal or other cancers. In this retrospective cohort study, we assessed risk of CRC and other cancers for the first- and second-degree relatives of CRC cases with a methylated MLH1 gene, by comparing observed numbers of cases with those expected on the basis of age-, sex-, and country-specific cancer incidences (standardized incidence ratios). The cohort consisted of 3,128 first- and second-degree relatives of the 233 MLH1-methylated CRC cases with no MMR or MUTYH gene mutations. The standardized incidence ratio (SIR) for CRC was 1.60 [95% confidence interval (CI), 1.22–2.16] for first-degree relatives and 1.08 (0.74–1.60) for second-degree relatives. The SIR for gastric cancer was 2.58 (1.52–4.71) for first-degree relatives and 4.52 (2.23–10.61) for second-degree relatives and, for ovarian cancer, it was 2.16 (1.29–3.86) for first-degree relatives. The risk of liver cancer was also increased significantly in first-degree relatives but the estimate was on the basis of only two cases. These data imply that relatives of CRC cases with MLH1 methylation may be at increased risk of CRC and stomach cancer and possibly ovarian and liver cancer, suggesting that there may be a heritable factor for CRC and other cancers associated with MLH1 methylation in non–Lynch syndrome CRCs. Cancer Prev Res; 5(2); 328–35. ©2011 AACR.
Using Stress Testing to Guide Primary Prevention of Coronary Heart Disease Among Intermediate-Risk Patients
Authors: Galper Benjamin Z. , Moran Andrew , Coxson Pamela G. , Pletcher Mark J. , Heidenreich Paul , Lazar Lawrence D. , Rodondi Nicolas , Wang Y. Claire , Goldman Lee 
Published: December 2011

Background—
Noninvasive stress testing might guide the use of aspirin and statins for primary prevention of coronary heart disease, but it is unclear if such a strategy would be cost effective.

Methods and Results—
We compared the status quo, in which the current national use of aspirin and statins was simulated, with 3 other strategies: (1) full implementation of Adult Treatment Panel III guidelines, (2) a treat-all strategy in which all intermediate-risk persons received statins (men and women) and aspirin (men only), and (3) a test-and-treat strategy in which all persons with an intermediate risk of coronary heart disease underwent stress testing and those with a positive test were treated with high-intensity statins (men and women) and aspirin (men only). Healthcare costs, coronary heart disease events, and quality-adjusted life years from 2011 to 2040 were projected. Under a variety of assumptions, the treat-all strategy was the most effective and least expensive strategy. Stress electrocardiography was more effective and less expensive than other test-and-treat strategies, but it was less expensive than treat all only if statin cost exceeded $3.16/pill or if testing increased adherence from <22% to >75%. However, stress electrocardiography could be cost effective in persons initially nonadherent to the treat-all strategy if it raised their adherence to 5% and cost saving if it raised their adherence to 13%.

Conclusions—
When generic high-potency statins are available, noninvasive cardiac stress testing to target preventive medications is not cost effective unless it substantially improves adherence.
A simple technique to prevent limb ischemia during veno-arterial ECMO using the femoral artery: the posterior tibial approach
Authors: Spurlock DJ , Toomasian JM , Romano MA , Cooley E , Bartlett RH , Haft JW 
Published: December 2011

Lower extremity ischemia is common when the femoral artery is used for veno-arterial extracorporeal membrane oxygenation (VA ECMO). We describe a new technique to reperfuse the extremity. The ipsilateral posterior tibial artery is exposed via a small incision behind the medial malleolus. The vessel is cannulated in a retrograde fashion and connected to the arterial limb of the ECMO circuit. Thirty-six patients received a posterior tibial reperfusion cannula: average flow was 155.8 ml/min and increased over the initial 24 hours. Fifty-eight percent received the posterior tibial cannula within 6 hours of ECMO initiation and none sustained permanent lower extremity injury. Of the remaining 42%, three required amputation or developed permanent neurologic injury. Overall survival was 41%. Cannulation of the posterior tibial artery is a simple technique to reperfuse the lower extremity during VA ECMO. The cannula should be inserted within 6 hours of ECMO initiation to avoid irreversible ischemic damage.
Awareness of incurable cancer status and health-related quality of life among advanced cancer patients: A prospective cohort study
Authors: Lee Myung Kyung , Baek Sun Kyung , Kim Si-young , Heo Dae Seog , Yun Young Ho , Park Sook Ryun , Kim Jun Suk 
Published: December 2011

Background: Many patients near death report an interest in knowing their prognoses. Patients’ awareness of disease status may lead to more appropriate care and maintained or improved quality of life. However, it is not known whether advanced cancer patients’ awareness of disease status is associated with patients’ quality of life. Aim: We aimed to examine the effect of patients’ awareness of disease status on the health-related quality of life (HRQOL) among advanced cancer patients undergoing palliative chemotherapy. Design: In this prospective cohort study, patients were followed-up at 4–6 weeks and 2–3 months after the initial palliative chemotherapy. Patients’ awareness of disease status, and demographic and clinical characteristics were assessed at baseline, and depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) and HRQOL using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were assessed three times. Setting / participants: In total, 100 patients with advanced cancer starting palliative chemotherapy were recruited from two tertiary university hospitals and from the Korea National Cancer Center. Results: Patients with advanced cancer undergoing palliative chemotherapy experienced deteriorated HRQOL. Of these, the patients who were aware of their disease status as incurable had significantly higher role ( p=0.002), emotional ( p=0.025), and social functioning ( p=0.002), and lower fatigue ( p=0.008), appetite loss ( p=0.039), constipation ( p=0.032), financial difficulties ( p=0.019), and anxiety ( p=0.041) compared with patients unaware of disease status. Conclusion: Our findings demonstrate the importance of patients’ awareness of disease status to HRQOL.
Social-cultural factors in end-of-life care in Belgium: A scoping of the research literature
Authors: Andrew Erin VW , Cohen Joachim , Evans Natalie , Meñaca Arantza , Harding Richard , Higginson Irene , Pool Robert , Gysels Marjolein 
Published: December 2011

Background: As end-of-life (EoL) care expands across Europe and the world, service developments are increasingly studied. The sociocultural context in which such changes take place, however, is often neglected in research. Aim: To explore sociocultural factors in EoL care in Belgium as represented by the literature. Design: A scoping of the empirical research literature following a systematic search procedure with a focus on thematic analysis based on the literature findings. Data sources: Searches were carried out in eight electronic databases, five journals, reference lists, and grey literature (through September 2010). Articles informing about sociocultural issues in EoL care were included. Results: One hundred and fifteen original studies met the inclusion criteria, the majority (107) published between 2000 and 2010. Four major themes were: Setting; Caregivers; Communication; and Medical EoL Decisions (the largest category). Minority Ethnic Groups was an emerging theme. Gaps included: research in Wallonia and Brussels; the role and experiences of informal caregivers; issues of access to palliative care; and experiences of minority ethnic groups. There was a paucity of in-depth qualitative studies. Conclusions: Various sociocultural factors influence the provision of EoL care in Belgium. This country provides a unique opportunity to witness how euthanasia is put into practice when legalized, in a context where palliative care is also highly developed and where many health care institutions have Catholic affiliation, providing an important example to others. Attention to how the sociocultural context affects EoL care adds to the current evidence base of service provision, which is essential in the further development of EoL care.
KATP channel openers in the trigeminovascular system
Authors: Ploug KB , Amrutkar DV , Baun M , Ramachandran R , Iversen A , Lund TM , Gupta S , Hay-Schmidt A , Olesen J , Jansen-Olesen I 
Published: December 2011

Background: The ATP-sensitive K+ (KATP) channel openers levcromakalim and pinacidil are vasodilators that induce headache in healthy people. The neuropeptide calcitonin gene-related peptide (CGRP) induces headache in healthy people and migraine in migraineurs, potentially through a mechanism that involves opening of vascular or neuronal KATP channels and mast cell degranulation. Using rat as a model, we studied the molecular presence of KATP channels in the trigeminovascular system. Furthermore, we examined whether KATP channel openers stimulate the in vitro release of CGRP and whether they degranulate dural mast cells. Methods: mRNA and protein expression of KATP channel subunits were studied in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) by qPCR and western blotting. In vitro CGRP release was studied after application of levcromakalim (1 µM) and diazoxide (10 µM) to freshly isolated rat dura mater, TG and TNC. Rat dural mast cells were challenged in situ with levcromakalim (10−5 M) to study its potential degranulation effect. Results: mRNA and protein of KATP channel subunits Kir6.1, Kir6.2, SUR1 and SUR2B were identified in the TG and TNC. KATP channel openers did not release or inhibit capsaicin-induced CGRP release from dura mater, TG or TNC. They did also not induce dural mast cell degranulation. Conclusions: KATP channel openers do not interact with CGRP release or mast cell degranulation. Activation of these channels in the CNS is antinociceptive and therefore cannot explain the headache induced by KATP channel openers. Thus, they are likely to induce headache by interaction with extracerebral KATP channels, probably the SUR2B isoforms.
Long-acting phosphodiesterase 5 inhibitor, tadalafil, and superoxide dismutase mimetic, tempol, protect against acute hypoxia-induced pulmonary hypertension in rats
Authors: Rashid M , Kotwani A , Fahim M 
Published: December 2011

Long-acting phosphodiesterase 5 (PDE5) inhibitor, tadalafil, was recently approved for the treatment of pulmonary hypertension. Apart from being a PDE5 inhibitor, tadalafil also possesses antioxidant activity. The aim of this study was to probe whether tadalafil has any beneficial effect over tempol owing to its antioxidant action in addition to PDE5 inhibitory activity. Albino Wistar rats were pretreated with tadalafil (10 mg/kg) or vehicle 2 h before hypoxic exposure, whereas tempol (20 mg/kg) was given 5 min before induction of hypoxia. Right ventricular systolic pressure (RVSP), mean arterial pressure (MAP), heart rate (HR), right ventricular contractility (RVd P/d tmax) and cardiac output (CO) were recorded while subjecting rats to acute hypoxia for 30 min. Lipid peroxidation and reduced glutathione were estimated in serum before and after hypoxia exposure. Tadalafil as well as tempol significantly prevented hypoxia-induced rise in RVSP ( p < 0.001) and RVd P/d tmax ( p < 0.05). Both tadalafil and tempol pretreatment partially prevented ( p < 0.01) the rise in CO due to hypoxia. Tadalafil did not produce any significant change in MAP, whereas tempol led to a significant fall ( p < 0.01) in MAP. Acute hypoxia increased the oxidative stress levels. Tadalafil pretreatment partially prevented hypoxia-induced oxidative stress, while tempol pretreatment completely prevented hypoxia-induced oxidative stress. Results suggest that tadalafil because of its antioxidant action in addition to PDE5 inhibitory activity is more appropriate for the prevention of hypoxic pulmonary hypertension than tempol. Tempol also produced undesirable systemic hypotension as side effect, which was not seen with tadalafil because of its pulmonary selective action.