bluuebunny/crossref_metadata_2025_split huggingface dataset:
Precise and scalable context-sensitive pointer analysis via value flow graph
Authors: Li Lian , Cifuentes Cristina , Keynes Nathan 
Published: December 2013

In this paper, we propose a novel method for context-sensitive pointer analysis using the value flow graph (VFG) formulation. We achieve context-sensitivity by simultaneously applying function cloning and computing context-free language reachability (CFL-reachability) in a novel way. In contrast to existing clone-based and CFL-based approaches, flow-sensitivity is easily integrated in our approach by using a flow-sensitive VFG where each value flow edge is computed in a flow-sensitive manner. We apply context-sensitivity to both local variables and heap objects and propose a new approximation for heap cloning.
We prove that our approach can achieve context-sensitivity without loss of precision, i.e., it is as precise as inlining all function calls. We develop an efficient algorithm and implement a context-, flow-, and field-sensitive pointer analysis with heap cloning support in LLVM. We evaluate the efficiency and precision of our implementation using standard SPEC CPU2006 benchmarks. Our experimental results show that the analysis is much faster than existing approaches, it scales well to large real-world applications, and it enables more effective compiler optimizations.
Metastatic Growth Progression Caused by PSGL-1–Mediated Recruitment of Monocytes to Metastatic Sites
Authors: Hoos Alexandra , Protsyuk Darya , Borsig Lubor 
Published: December 2013

Abstract
Tumor cell–derived selectin ligands mediate contact to the endothelium, platelets, and leukocytes through binding to selectins that facilitates metastasis. Here, we describe the mechanism of how endogenous (non–tumor derived) selectin ligands contribute to metastasis using α(1,3)fucosyltransferase 7 (Fuc-TVII−/−)–deficient mice. Experimental metastasis of MC-38GFP and Lewis lung (3LL) carcinoma cells was attenuated in Fuc-TVII−/− mice, which express minimal amount of selectin ligands. We show that metastasis is dependent on selectin ligands carried on hematopoietic cells. P-selectin glycoprotein ligand-1 (PSGL-1) was identified as the major ligand facilitating monocyte accumulation at metastatic sites. Reduced recruitment of monocytes to metastasizing tumor cells in Fuc-TVII−/− mice correlated with attenuated metastasis. Adoptive transfer of Fuc-T7+ monocytes rescued metastasis in Fuc-TVII−/− mice, indicating that selectin ligand–dependent recruitment of monocytes is required for cancer progression. Cytokine analysis in metastatic lungs revealed high expression of CCL2 in C57BL/6 mice that was significantly lower in Fuc-TVII−/− mice. The absence of monocyte recruitment in Fuc-TVII−/− mice correlated with increased apoptosis of tumor cells. Thus, the recruitment of monocytes to metastasizing tumor cells is facilitated by endogenous selectin ligands on monocytes that enable efficient tumor cell survival, extravasation, and metastasis. Cancer Res; 74(3); 695–704. ©2013 AACR.
Cancer-Derived Mutations in KEAP1 Impair NRF2 Degradation but not Ubiquitination
Authors: Hast Bridgid E. , Cloer Erica W. , Goldfarb Dennis , Li Heng , Siesser Priscila F. , Yan Feng , Walter Vonn , Zheng Ning , Hayes D. Neil , Major Michael B. 
Published: December 2013

Abstract
NRF2 is a transcription factor that mediates stress responses. Oncogenic mutations in NRF2 localize to one of its two binding interfaces with KEAP1, an E3 ubiquitin ligase that promotes proteasome-dependent degradation of NRF2. Somatic mutations in KEAP1 occur commonly in human cancer, where KEAP1 may function as a tumor suppressor. These mutations distribute throughout the KEAP1 protein but little is known about their functional impact. In this study, we characterized 18 KEAP1 mutations defined in a lung squamous cell carcinoma tumor set. Four mutations behaved as wild-type KEAP1, thus are likely passenger events. R554Q, W544C, N469fs, P318fs, and G333C mutations attenuated binding and suppression of NRF2 activity. The remaining mutations exhibited hypomorphic suppression of NRF2, binding both NRF2 and CUL3. Proteomic analysis revealed that the R320Q, R470C, G423V, D422N, G186R, S243C, and V155F mutations augmented the binding of KEAP1 and NRF2. Intriguingly, these “super-binder” mutants exhibited reduced degradation of NRF2. Cell-based and in vitro biochemical analyses demonstrated that despite its inability to suppress NRF2 activity, the R320Q “superbinder” mutant maintained the ability to ubiquitinate NRF2. These data strengthen the genetic interactions between KEAP1 and NRF2 in cancer and provide new insight into KEAP1 mechanics. Cancer Res; 74(3); 808–17. ©2013 AACR.
Adaptive Prediction Model in Prospective Molecular Signature–Based Clinical Studies
Authors: Xiao Guanghua , Ma Shuangge , Minna John , Xie Yang 
Published: December 2013

Abstract
Use of molecular profiles and clinical information can help predict which treatment would give the best outcome and survival for each individual patient, and thus guide optimal therapy, which offers great promise for the future of clinical trials and practice. High prediction accuracy is essential for selecting the best treatment plan. The gold standard for evaluating the prediction models is prospective clinical studies, in which patients are enrolled sequentially. However, there is no statistical method using this sequential feature to adapt the prediction model to the current patient cohort. In this article, we propose a reweighted random forest (RWRF) model, which updates the weight of each decision tree whenever additional patient information is available, to account for the potential heterogeneity between training and testing data. A simulation study and a lung cancer example are used to show that the proposed method can adapt the prediction model to current patients' characteristics, and, therefore, can improve prediction accuracy significantly. We also show that the proposed method can identify important and consistent predictive variables. Compared with rebuilding the prediction model, the RWRF updates a well-tested model gradually, and all of the adaptive procedure/parameters used in the RWRF model are prespecified before patient recruitment, which are important practical advantages for prospective clinical studies. Clin Cancer Res; 20(3); 531–9. ©2013 AACR.
Surveillance of the Tumor Mutanome by T Cells during Progression from Primary to Recurrent Ovarian Cancer
Authors: Wick Darin A. , Webb John R. , Nielsen Julie S. , Martin Spencer D. , Kroeger David R. , Milne Katy , Castellarin Mauro , Twumasi-Boateng Kwame , Watson Peter H. , Holt Rob A. , Nelson Brad H. 
Published: December 2013

AbstractPurpose: Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in patients with ovarian cancer undergoing standard treatment.Experimental Design: Tumor-associated T cells from 3 patients with ovarian cancer were assessed by ELISPOT for recognition of nonsynonymous mutations identified by whole exome sequencing of autologous tumor. The relative levels of mutations and responding T cells were monitored in serial tumor samples collected at primary surgery and first and second recurrence.Results: The vast majority of mutations (78/79) were not recognized by tumor-associated T cells; however, a highly specific CD8+ T-cell response to the mutation hydroxysteroid dehydrogenase–like protein 1 (HSDL1)L25V was detected in one patient. In the primary tumor, the HSDL1L25V mutation had low prevalence and expression, and a corresponding T-cell response was undetectable. At first recurrence, there was a striking increase in the abundance of the mutation and corresponding MHC class I epitope, and this was accompanied by the emergence of the HSDL1L25V-specific CD8+ T-cell response. At second recurrence, the HSDL1L25V mutation and epitope continued to be expressed; however, the corresponding T-cell response was no longer detectable.Conclusion: The immune system can respond to the evolving ovarian cancer genome. However, the T-cell response detected here was rare, was transient, and ultimately failed to prevent disease progression. These findings reveal the limitations of spontaneous tumor immunity in the setting of standard treatments and suggest a high degree of ignorance of tumor mutations that could potentially be reversed by immunotherapy. Clin Cancer Res; 20(5); 1125–34. ©2013 AACR.
Dynamic Interplay of Oncogenes and T Cells Induces PD-L1 in the Tumor Microenvironment
Authors: Rech Andrew J. , Vonderheide Robert H. 
Published: December 2013

Abstract
Summary: Tumor-infiltrating T cells have recently been found to upregulate immunosuppressive pathways, such as programmed cell death protein 1 ligand 1 (PD-L1), in a paracrine fashion on tumor cells, but tumor cell–intrinsic regulation of PD-L1 is another potential mechanism. In this issue of Cancer Discovery, Akbay and colleagues show that signaling via mutant EGF receptor (EGFR) in murine lung tumor cells directly upregulates tumor PD-L1 and that therapeutic blockade of this pathway improves survival in EGFR-driven preclinical models—highlighting the dynamic interplay and therapeutic opportunities of cancer cell biology and immune biology. Cancer Discov; 3(12); 1330–2. ©2013 AACR.
See related article by Akbay et al., p. 1355
Cardiovascular Events Associated With Smoking Cessation Pharmacotherapies
Authors: Mills Edward J. , Thorlund Kristian , Eapen Shawn , Wu Ping , Prochaska Judith J. 
Published: December 2013

Background—
Stopping smoking is associated with many important improvements in health and quality of life. The use of cessation medications is recommended to increase the likelihood of quitting. However, there is historical and renewed concern that smoking cessation therapies may increase the risk of cardiovascular disease events associated within the quitting period. We aimed to examine whether the 3 licensed smoking cessation therapies—nicotine replacement therapy, bupropion, and varenicline—were associated with an increased risk of cardiovascular disease events using a network meta-analysis.

Methods and Results—
We searched 10 electronic databases, were in communication with authors of published randomized, clinical trials (RCTs), and accessed internal US Food and Drug Administration reports. We included any RCT of the 3 treatments that reported cardiovascular disease outcomes. Among 63 eligible RCTs involving 21 nicotine replacement therapy RCTs, 28 bupropion RCTs, and 18 varenicline RCTs, we found no increase in the risk of all cardiovascular disease events with bupropion (relative risk [RR], 0.98; 95% confidence interval [CI], 0.54–1.73) or varenicline (RR, 1.30; 95% CI, 0.79–2.23). There was an elevated risk associated with nicotine replacement therapy that was driven predominantly by less serious events (RR, 2.29; 95% CI, 1.39–3.82). When we examined major adverse cardiovascular events, we found a protective effect with bupropion (RR, 0.45; 95% CI, 0.21–0.85) and no clear evidence of harm with varenicline (RR, 1.34; 95% CI, 0.66–2.66) or nicotine replacement therapy (RR, 1.95; 95% CI, 0.26–4.30).

Conclusion—
Smoking cessation therapies do not appear to raise the risk of serious cardiovascular disease events.
Differentiation of pleomorphic adenoma and Warthin’s tumor of the parotid gland: ultrasonographic features
Authors: Rong Xueyu , Zhu Qiang , Ji Hongtao , Li Jiangping , Huang Huilian 
Published: December 2013

BackgroundParotid tumor is an uncommon neoplasm. Only a few studies describing the sonographic features of pleomorphic adenomas and Warthin’s tumors have been published, and most of those reports are based on a relatively small number of cases.PurposeTo define the sonographic characteristics of pleomorphic adenoma and Warthin’s tumor in the parotid gland.Material and MethodsWe retrospectively evaluated the sonographic features of 77 pleomorphic adenomas in 70 patients and 93 Warthin’s tumors in 61 patients. The features included tumor size, shape, border, echogenicity, and homogeneity, the presence of a cystic area, acoustic enhancement, and the grade and distribution of vascularization.ResultsLobulated lesions were observed in 49 pleomorphic adenomas and 36 Warthin’s tumors. The lobulated shape was observed more frequently in pleomorphic adenomas than in Warthin’s tumors ( P = 0.005). Cystic areas within lesions were detected in 16 (16/77, 20.8%) pleomorphic adenomas and 42 (42/93, 45.2%) Warthin’s tumors ( P = 0.001). Of the pleomorphic adenomas, 77.9% had grade 0 or grade 1 vascularity, while 73.1% of Warthin’s tumors had grade 2 or grade 3 vascularity ( P = 0.000). Flow was peripheral in 53.2% of pleomorphic adenomas. The frequencies of central perfusion and mixed perfusion in Warthin’s tumors were equal (47.3% vs. 47.3%, respectively). The differences in the vessel distribution between these two diseases was significant ( P = 0.000).ConclusionUltrasound imaging characteristics, including multiple occurrences, shape, intrinsic cystic change, and the grade and distribution of tumor vessels, can be used to differentiate pleomorphic adenomas from Warthin’s tumors.
Disability, anxiety and depression associated with medication-overuse headache can be considerably reduced by detoxification and prophylactic treatment. Results from a multicentre, multinational study (COMOESTAS project)
Authors: Bendtsen L , Munksgaard SB , Tassorelli C , Nappi G , Katsarava Z , Lainez M , Leston JA , Fadic R , Spadafora S , Stoppini A , Jensen R ,   the COMOESTAS Consortium
Published: December 2013

Objective The objective of this article is to investigate whether headache-related disability, depression and anxiety can be reduced by detoxification and prophylactic treatment in patients with medication-overuse headache (MOH). Methods Patients with MOH were included from six centres in Europe and Latin America in a seven-month cohort study. Before and six months after treatment, the degree of disability was measured by the Migraine Disability Assessment (MIDAS) questionnaire, while anxiety and depression were measured by the Hospital Anxiety and Depression Scale (HADS). Results A total of 694 patients with MOH were included, of whom 492 completed the study. Headache days were reduced by 58.4% from 23.6 to 9.8 days per month at six months ( p < 0.001). The MIDAS score was reduced by 57.1% from baseline 59.9 to 25.7 ( p < 0.001). Number of patients with depression was reduced by 50.7% from 195 to 96 and number of those with anxiety was reduced by 27.1% from 284 to 207 (both p < 0.001). Conclusions Disability, depression and anxiety were considerably reduced in patients with MOH by detoxification and prophylactic treatment. This emphasises the urgent need for increased awareness about avoiding overuse of headache medications and demonstrates that not only headache frequency but also disability are remarkably improved by adequate intervention.
Association of homocysteine with type 2 diabetes: a meta-analysis implementing Mendelian randomization approach
Authors: Huang Tao , Ren JingJing , Huang Jinyan , Li Duo 
Published: December 2013

Abstract

Background
We tested the hypothesis that elevated homocysteine (Hcy) level is causally associated with increased risk of type 2 diabetes mellitus (T2DM).

Results
The meta-analysis and Mendelian randomization analysis were performed among 4011 cases and 4303 controls. The absolute pooled mean Hcy concentration in subjects with MTHFR 677TT was 5.55 μmol/L (95% CI, 1.33 to 9.77) greater than that in subjects with MTHFR 677CC in T2DM. Overall, the T allele of the MTHFR 677 C > T conferred a greater risk for T2DM [Random effect (RE) OR = 1.31(1.17-1.64), I2 = 41.0%, p = 0.055]. The random effect (RE) pooled OR associated with T2DM for MTHFR 677TT relative to the 677CC was [RE OR = 1.38(1.18-1.62)]. The fixed-effect pooled OR of the association for the MTHFR 677 TT vs CT was 1.29 (95% CI, 1.09-1.51). MTHFR 677 TT showed a significantly higher risk for T2DM compared with MTHFR 677 CC + CT [Fixed effect (FE) OR = 1.32(1.14-1.54), I2 = 0.0%, p = 0.686]. The absolute pooled mean Hcy concentration in individuals with T2DM was 0.94 μmol/L (95% CI, 0.40-1.48) greater than that in control subjects. The estimated causal OR associated with T2DM was 1.29 for 5 μmol/L increment in Hcy.

Conclusions
Our findings provided strong evidence on the causal association of Hcy level with the development of T2DM.
An assessment of existing models for individualized breast cancer risk estimation in a screening program in Spain
Authors: Arrospide Arantzazu , Forné Carles , Rué Montse , Torà Núria , Mar Javier , Baré Marisa 
Published: December 2013

Abstract

Background
The aim of this study was to evaluate the calibration and discriminatory power of three predictive models of breast cancer risk.

Methods
We included 13,760 women who were first-time participants in the Sabadell-Cerdanyola Breast Cancer Screening Program, in Catalonia, Spain. Projections of risk were obtained at three and five years for invasive cancer using the Gail, Chen and Barlow models. Incidence and mortality data were obtained from the Catalan registries. The calibration and discrimination of the models were assessed using the Hosmer-Lemeshow C statistic, the area under the receiver operating characteristic curve (AUC) and the Harrell’s C statistic.

Results
The Gail and Chen models showed good calibration while the Barlow model overestimated the number of cases: the ratio between estimated and observed values at 5 years ranged from 0.86 to 1.55 for the first two models and from 1.82 to 3.44 for the Barlow model. The 5-year projection for the Chen and Barlow models had the highest discrimination, with an AUC around 0.58. The Harrell’s C statistic showed very similar values in the 5-year projection for each of the models. Although they passed the calibration test, the Gail and Chen models overestimated the number of cases in some breast density categories.

Conclusions
These models cannot be used as a measure of individual risk in early detection programs to customize screening strategies. The inclusion of longitudinal measures of breast density or other risk factors in joint models of survival and longitudinal data may be a step towards personalized early detection of BC.
Effect of dynamic random leaks on the monitoring accuracy of home mechanical ventilators: a bench study
Authors: Sogo Ana , Montanyà Jaume , Monsó Eduard , Blanch Lluís , Pomares Xavier , Lujàn Manel 
Published: December 2013

Abstract

Background
So far, the accuracy of tidal volume (VT) and leak measures provided by the built-in software of commercial home ventilators has only been tested using bench linear models with fixed calibrated and continuous leaks. The objective was to assess the reliability of the estimation of tidal volume (VT) and unintentional leaks in a single tubing bench model which introduces random dynamic leaks during inspiratory or expiratory phases.

Methods
The built-in software of four commercial home ventilators and a fifth ventilator-independent ad hoc designed external software tool were tested with two levels of leaks and two different models with excess leaks (inspiration or expiration). The external software analyzed separately the inspiratory and expiratory unintentional leaks.

Results
In basal condition, all ventilators but one underestimated tidal volume with values ranging between -1.5 ± 3.3% to -8.7% ± 3.27%. In the model with excess of inspiratory leaks, VT was overestimated by all four commercial software tools, with values ranging from 18.27 ± 7.05% to 35.92 ± 17.7%, whereas the ventilator independent-software gave a smaller difference (3.03 ± 2.6%). Leaks were underestimated by two applications with values of -11.47 ± 6.32 and -5.9 ± 0.52 L/min. With expiratory leaks, VT was overestimated by the software of one ventilator and the ventilator-independent software and significantly underestimated by the other three, with deviations ranging from +10.94 ± 7.1 to -48 ± 23.08%. The four commercial tools tested overestimated unintentional leaks, with values between 2.19 ± 0.85 to 3.08 ± 0.43 L/min.

Conclusions
In a bench model, the presence of unintentional random leaks may be a source of error in the measurement of VT and leaks provided by the software of home ventilators. Analyzing leaks during inspiration and expiration separately may reduce this source of error.
Norartocarpetin from a folk medicine Artocarpus communis plays a melanogenesis inhibitor without cytotoxicity in B16F10 cell and skin irritation in mice
Authors: Ko Horng-Huey , Tsai Yi-Ting , Yen Ming-Hong , Lin Chun-Ching , Liang Chan-Jung , Yang Tsung-Han , Lee Chiang-Wen , Yen Feng-Lin 
Published: December 2013

AbstractBackgroundMany natural products used in preventive medicine have also been developed as cosmeceutical ingredients in skin care products, such asScutellaria baicalensisandGardenia jasminoides. Norartocarpetin is one of the antioxidant and antityrosinase activity compound inArtocarpus communis; however, the cytotoxicity, skin irritation and antimelanogenesis mechanisms of norartocarpetin have not been investigated yet.MethodsIn the present study, cell viabilityin vitroand skin irritationin vivoare used to determine the safety of norartocarpetin. The melanogenesis inhibition of norartocarpetin was determined by cellular melanin content and tyrosinase in B16F10 melanoma cell. Moreover, we examined the related-melanogenesis protein by western blot analysis for elucidating the antimelanogenesis mechanism of norartocarpin.ResultsThe result of the present study demonstrated that norartocarpetin not only present non-cytotoxic in B16F10 and human fibroblast cells but also non-skin irritation in mice. Moreover, our result also first found that norartocarpetin downregulated phospho-cAMP response element-binding (phospho-CREB) and microphthalmia-associated transcription factor (MITF) expression, which in turn decreased both synthesis of tyrosinases (TRP-1 and TRP-2) and cellular melanin content. This process is dependent on norartocarpetin phosphorylation by mitogen-activated protein kinases such as phospho-JNK and phospho-p38, and it results in decreased melanogenesis.ConclusionThe present study suggests that norartocarpetin could be used as a whitening agent in medicine and/or cosmetic industry and need further clinical study.
Expression of MACC1 and c-Met in human gastric cancer and its clinical significance
Authors: Guo Tiankang , Yang Jingyu , Yao Jibin , Zhang Yongbin , Da Mingxu , Duan Yaoxing 
Published: December 2013

Abstract

Background
Recent studies have suggested that the metastasis-associated colon cancer1 (MACC1) gene can promote tumor proliferation, invasion and metastasis through an upregulation of c-Met expression. However, its role in gastric cancer is controversial. Our study investigated expression of MACC1 and c-Met in gastric cancer, as well as correlated this with clinicopathological parameters.

Methods
Expressions of MACC1 and c-Met protein in a sample of 98 gastric carcinoma and adjacent nontumorous tissues were detected by immunohistochemistry. Their relationships and correlations with clinicopathological features were analyzed.

Results
The positive rates of MACC1 and c-Met protein in primary tumors were 61.22% and 59.18%, respectively. A significant correlation was found between expression of MACC1 and c-Met (P<0.05). Expression of the MACC1 protein in gastric cancer tissue was correlated with lymph node metastasis (χ2 = 10.555,P = 0.001), peritoneal metastasis (χ2 = 5.694, P = 0.017), and hepatic metastasis (χ2 = 4.540,P = 0.033), but not with age, gender, tumor size, location, clinical stage or the distant metastases (P>0.05).

Conclusion
The positive rate of MACC1 protein expression was related to the protein expression of c-Met. Both had a correlation with the presence of peritoneal metastasis, lymph node metastasis and hepatic metastasis, all of which contribute to a poor prognosis for gastric cancer patients.