bluuebunny/crossref_metadata_2025_split huggingface dataset:
Informing the ‘early years’ agenda in Scotland: understanding infant feeding patterns using linked datasets
Authors: Ajetunmobi Omotomilola , Whyte Bruce , Chalmers James , Fleming Michael , Stockton Diane , Wood Rachel 
Published: October 2013

BackgroundProviding infants with the ‘best possible start in life’ is a priority for the Scottish Government. This is reflected in policy and health promotion strategies to increase breast feeding, which gives the best source of nutrients for healthy infant growth and development. However, the rate of breast feeding in Scotland remains one of the lowest in Europe. Information is needed to provide a better understanding of infant feeding and its impact on child health. This paper describes the development of a unique population-wide resource created to explore infant feeding and child health in Scotland.MethodsDescriptive and multivariate analyses of linked routine/administrative maternal and infant health records for 731 595 infants born in Scotland between 1997 and 2009.ResultsA linked dataset was created containing a wide range of background, parental, maternal, birth and health service characteristics for a representative sample of infants born in Scotland over the study period. There was high coverage and completeness of infant feeding and other demographic, maternal and infant records. The results confirmed the importance of an enabling environment—cultural, family, health service and other maternal and infant health-related factors—in increasing the likelihood to breast feed.ConclusionsUsing the linked dataset, it was possible to investigate the determinants of breast feeding for a representative sample of Scottish infants born between 1997 and 2009. The linked dataset is an important resource that has potential uses in research, policy design and targeting intervention programmes.
Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK
Authors: Doma Eszter , Rupp Christian , Varga Andrea , Kern Florian , Riegler Bettina , Baccarini Manuela 
Published: October 2013

Abstract
RAF inhibitors achieve unprecedented but mainly transient clinical responses in patients with melanoma whose tumors harbor an activating BRAF mutation. One notable side-effect of RAF inhibitors is the stimulation of cutaneous skin tumors, arising in about 30% of patients receiving these drugs, which are thought to develop as a result of inhibitor-induced activation of wild-type Raf in occult precursor skin lesions. This effect raises the possibility that less manageable tumors might also arise in other epithelial tissues. Here we provide preclinical evidence supporting this disquieting hypothesis by showing that the RAF inhibitors PLX-4032 (vemurafenib) and GDC-0879 precipitate the development of cell-autonomous, Ras-driven tumors in skin and gastric epithelia. The magnitude of the effects correlated with the inhibitors' relative abilities to induce ERK activation. Epidermis-restricted ablation of either B-Raf or C-Raf prevented PLX-4032–induced ERK activation and tumorigenesis. In contrast, GDC-0879 induced ERK activation and tumorigenesis in B-Raf–deficient epidermis, whereas C-Raf ablation blocked GDC-0879–induced tumorigenesis (despite strong ERK activation) by preventing Rokα–mediated keratinocyte dedifferentiation. Thus, inhibitor-induced ERK activation did not require a specific Raf kinase. ERK activation was necessary, but not sufficient for Ras + Raf inhibitor-induced tumorigenesis, whereas C-Raf downregulation of Rokα was essential even in the face of sustained ERK signaling to prevent differentiation and promote tumorigenesis. Taken together, our findings suggest that combination therapies targeting ERK-dependent and -independent functions of Raf may be more efficient but also safer for cancer treatment. Cancer Res; 73(23); 6926–37. ©2013 AACR.
Epigenetic Inactivation of microRNA-34b/c Predicts Poor Disease-Free Survival in Early-Stage Lung Adenocarcinoma
Authors: Nadal Ernest , Chen Guoan , Gallegos Marc , Lin Lin , Ferrer-Torres Daysha , Truini Anna , Wang Zhuwen , Lin Jules , Reddy Rishindra M. , Llatjos Roger , Escobar Ignacio , Moya Juan , Chang Andrew C. , Cardenal Felipe , Capellà Gabriel , Beer David G. 
Published: October 2013

Abstract
Purpose: The microRNA-34b/c (miR-34b/c) is considered a tumor suppressor in different tumor types and a transcriptional target of TP53. The main objectives of this study were to investigate the clinical implications of miR-34b/c methylation in patients with early-stage lung adenocarcinoma and to determine the functional role of miR-34b/c re-expression in lung adenocarcinoma cell lines.
Experimental Design: Aberrant methylation and expression of miR-34b/c were assessed in 15 lung adenocarcinoma cell lines and a cohort of 140 early-stage lung adenocarcinoma. Lung adenocarcinoma cell lines were transfected with miR-34b/c and the effects upon cell proliferation, migration, invasion, and apoptosis were investigated.
Results: Aberrant methylation of miR-34b/c was detected in 6 (40%) of 15 lung adenocarcinoma cell lines and 64 of 140 (46%) primary lung adenocarcinoma. Expression of miR-34b/c was significantly reduced in all methylated cell lines and primary tumors, especially with TP53 mutations. Patients with increased miR-34b/c methylation had significantly shorter disease-free and overall survival as compared to patients with unmethylated or low level of miR-34b/c methylation. Ectopic expression of miR-34b/c in lung adenocarcinoma cell lines decreased cell proliferation, migration, and invasion.
Conclusions: Epigenetic inactivation of miR-34b/c by DNA methylation has independent prognostic value in patients with early-stage lung adenocarcinoma. Reexpression of miR-34b/c leads to a less aggressive phenotype in lung adenocarcinoma cell lines. Clin Cancer Res; 19(24); 6842–52. ©2013 AACR.
A Comparative Analysis of Prognostic Factor Models for Follicular Lymphoma Based on a Phase III Trial of CHOP–Rituximab versus CHOP + 131Iodine—Tositumomab
Authors: Press Oliver W. , Unger Joseph M. , Rimsza Lisa M. , Friedberg Jonathan W. , LeBlanc Michael , Czuczman Myron S. , Kaminski Mark , Braziel Rita M. , Spier Catherine , Gopal Ajay K. , Maloney David G. , Cheson Bruce D. , Dakhil Shaker R. , Miller Thomas P. , Fisher Richard I. 
Published: October 2013

Abstract
Purpose: There is currently no consensus on optimal frontline therapy for patients with follicular lymphoma. We analyzed a phase III randomized intergroup trial comparing six cycles of CHOP-R (cyclophosphamide–Adriamycin–vincristine–prednisone (Oncovin)–rituximab) with six cycles of CHOP followed by iodine-131 tositumomab radioimmunotherapy (RIT) to assess whether any subsets benefited more from one treatment or the other, and to compare three prognostic models.
Experimental Design: We conducted univariate and multivariate Cox regression analyses of 532 patients enrolled on this trial and compared the prognostic value of the FLIPI (follicular lymphoma international prognostic index), FLIPI2, and LDH + β2M (lactate dehydrogenase + β2-microglobulin) models.
Results: Outcomes were excellent, but not statistically different between the two study arms [5-year progression-free survival (PFS) of 60% with CHOP-R and 66% with CHOP-RIT (P = 0.11); 5-year overall survival (OS) of 92% with CHOP-R and 86% with CHOP-RIT (P = 0.08); overall response rate of 84% for both arms]. The only factor found to potentially predict the impact of treatment was serum β2M; among patients with normal β2M, CHOP-RIT patients had better PFS compared with CHOP-R patients, whereas among patients with high serum β2M, PFS by arm was similar (interaction P value = 0.02).
Conclusions: All three prognostic models (FLIPI, FLIPI2, and LDH + β2M) predicted both PFS and OS well, though the LDH + β2M model is easiest to apply and identified an especially poor risk subset. In an exploratory analysis using the latter model, there was a statistically significant trend suggesting that low-risk patients had superior observed PFS if treated with CHOP-RIT, whereas high-risk patients had a better PFS with CHOP-R. Clin Cancer Res; 19(23); 6624–32. ©2013 AACR.
Small-Molecule Inhibitors of USP1 Target ID1 Degradation in Leukemic Cells
Authors: Mistry Helena , Hsieh Grace , Buhrlage Sara J. , Huang Min , Park Eunmi , Cuny Gregory D. , Galinsky Ilene , Stone Richard M. , Gray Nathanael S. , D'Andrea Alan D. , Parmar Kalindi 
Published: October 2013

Abstract
Inhibitor of DNA binding 1 (ID1) transcription factor is essential for the proliferation and progression of many cancer types, including leukemia. However, the ID1 protein has not yet been therapeutically targeted in leukemia. ID1 is normally polyubiquitinated and degraded by the proteasome. Recently, it has been shown that USP1, a ubiquitin-specific protease, deubiquitinates ID1 and rescues it from proteasome degradation. Inhibition of USP1 therefore offers a new avenue to target ID1 in cancer. Here, using a ubiquitin-rhodamine–based high-throughput screening, we identified small-molecule inhibitors of USP1 and investigated their therapeutic potential for leukemia. These inhibitors blocked the deubiquitinating enzyme activity of USP1 in vitro in a dose-dependent manner with an IC50 in the high nanomolar range. USP1 inhibitors promoted the degradation of ID1 and, concurrently, inhibited the growth of leukemic cell lines in a dose-dependent manner. A known USP1 inhibitor, pimozide, also promoted ID1 degradation and inhibited growth of leukemic cells. In addition, the growth of primary acute myelogenous leukemia (AML) patient-derived leukemic cells was inhibited by a USP1 inhibitor. Collectively, these results indicate that the novel small-molecule inhibitors of USP1 promote ID1 degradation and are cytotoxic to leukemic cells. The identification of USP1 inhibitors therefore opens up a new approach for leukemia therapy. Mol Cancer Ther; 12(12); 2651–62. ©2013 AACR.
Tunicamycin Potentiates Cisplatin Anticancer Efficacy through the DPAGT1/Akt/ABCG2 Pathway in Mouse Xenograft Models of Human Hepatocellular Carcinoma
Authors: Hou Helei , Sun Hefen , Lu Ping , Ge Chao , Zhang Lixing , Li Hong , Zhao Fangyu , Tian Hua , Zhang Lin , Chen Taoyang , Yao Ming , Li Jinjun 
Published: October 2013

AbstractHepatocellular carcinoma is highly chemoresistant, and ATP-binding cassette subfamily G member 2 (ABCG2) is thought to play a critical role in this drug resistance. The present study aims to develop effective therapeutic strategies to decrease ABCG2 expression level and to surmount drug resistance in hepatocellular carcinoma chemotherapy. First, we verified a positive correlation between the ABCG2 protein level and the drug resistance of hepatocellular carcinoma cell lines. ABCG2 was preferentially expressed in highly chemoresistant hepatocellular carcinoma cancer stem cells (CSC) enriched with CD133. In addition, ABCG2 was N-linked glycosylated in hepatocellular carcinoma cells, and this modification was involved in sustaining its protein stability. The N-linked glycosylation (NLG) inhibitor tunicamycin dramatically reduced ABCG2 expression, altered its subcellular localization, and reversed its drug efflux effect in multiple hepatocellular carcinoma cell lines. Furthermore, tunicamycin reduced the expression levels of several CSC markers and suppressed the tumorigenicity of CD133+ CSCs. Tunicamycin combined with cisplatin (CDDP) inhibited proliferating cell nuclear antigen (PCNA) expression and increased the cleavage of PARP; this effect was partially rescued by the overexpression of ABCG2 or Akt-myr. The combination therapy more effectively suppressed tumor growth in xenograft mice than did single-agent therapy with either drug. Finally, the CDDP treatment combined with UDP-GlcNAc-dolichol-phosphate N-acetylglucosamine-1 phosphate transferase (DPAGT1) knockdown recapitulated the effect observed when CDDP was used in combination with tunicamycin. In summary, our results suggest that tunicamycin may reverse the drug resistance and improve the efficacy of combination treatments for hepatocellular carcinomas by targeting the DPAGT1/Akt/ABCG2 pathway. Mol Cancer Ther; 12(12); 2874–84. ©2013 AACR.
Dual HER/VEGF Receptor Targeting Inhibits In Vivo Ovarian Cancer Tumor Growth
Authors: Becker Marc A. , Farzan Thahir , Harrington Sean C. , Krempski James W. , Weroha S. John , Hou Xiaonan , Kalli Kimberly R. , Wong Tai W. , Haluska Paul 
Published: October 2013

Abstract
Ovarian cancer mortality ranks highest among all gynecologic cancers with growth factor pathways playing an integral role in tumorigenesis, metastatic dissemination, and therapeutic resistance. The HER and VEGF receptor (VEGFR) are both overexpressed and/or aberrantly activated in subsets of ovarian tumors. While agents targeting either the HER or VEGF pathways alone have been investigated, the impact of these agents have not led to overall survival benefit in ovarian cancer. We tested the hypothesis that cotargeting HER and VEGFR would maximize antitumor efficacy at tolerable doses. To this end, ovarian cancer xenografts grown intraperitoneally in athymic nude mice were tested in response to AC480 (pan-HER inhibitor, “HERi”), cediranib (pan-VEGFR inhibitor “VEGFRi”), or BMS-690514 (combined HER/VEGFR inhibitor “EVRi”). EVRi was superior to both HERi and VEGFRi in terms of tumor growth, final tumor weight, and progression-free survival. Correlative tumor studies employing phosphoproteomic antibody arrays revealed distinct agent-specific alterations, with EVRi inducing the greatest overall effect on growth factor signaling. These data suggest that simultaneous inhibition of HER and VEGFR may benefit select subsets of ovarian cancer tumors. To this end, we derived a novel HER/VEGF signature that correlated with poor overall survival in high-grade, late stage, serous ovarian cancer patient tumors. Mol Cancer Ther; 12(12); 2909–16. ©2013 AACR.
Cardiovascular Effects of 1 Year of Alagebrium and Endurance Exercise Training in Healthy Older Individuals
Authors: Fujimoto Naoki , Hastings Jeffrey L. , Carrick-Ranson Graeme , Shafer Keri M. , Shibata Shigeki , Bhella Paul S. , Abdullah Shuaib M. , Barkley Kyler W. , Adams-Huet Beverley , Boyd Kara N. , Livingston Sheryl A. , Palmer Dean , Levine Benjamin D. 
Published: October 2013

Background—
Lifelong exercise training maintains a youthful compliance of the left ventricle (LV), whereas a year of exercise training started later in life fails to reverse LV stiffening, possibly because of accumulation of irreversible advanced glycation end products. Alagebrium breaks advanced glycation end product crosslinks and improves LV stiffness in aged animals. However, it is unclear whether a strategy of exercise combined with alagebrium would improve LV stiffness in sedentary older humans.

Methods and Results—

Sixty-two healthy subjects were randomized into 4 groups: sedentary+placebo; sedentary+alagebrium (200 mg/d); exercise+placebo; and exercise+alagebrium. Subjects underwent right heart catheterization to define LV pressure–volume curves; secondary functional outcomes included cardiopulmonary exercise testing and arterial compliance. A total of 57 of 62 subjects (67±6 years; 37 f/20 m) completed 1 year of intervention followed by repeat measurements. Pulmonary capillary wedge pressure and LV end-diastolic volume were measured at baseline, during decreased and increased cardiac filling. LV stiffness was assessed by the slope of LV pressure–volume curve. After intervention, LV mass and end-diastolic volume increased and exercise capacity improved (by ≈8%) only in the exercise groups. Neither LV mass nor exercise capacity was affected by alagebrium. Exercise training had little impact on LV stiffness (training×time effect,
P
=0.46), whereas alagebrium showed a modest improvement in LV stiffness compared with placebo (medication×time effect,
P
=0.04).

Conclusions—
Alagebrium had no effect on hemodynamics, LV geometry, or exercise capacity in healthy, previously sedentary seniors. However, it did show a modestly favorable effect on age-associated LV stiffening.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01014572.
Cognitive Trajectory After Transcatheter Aortic Valve Implantation
Authors: Ghanem Alexander , Kocurek Justine , Sinning Jan-Malte , Wagner Michael , Becker Benjamin V. , Vogel Marieke , Schröder Thomas , Wolfsgruber Steffen , Vasa-Nicotera Mariuca , Hammerstingl Christoph , Schwab Jörg O. , Thomas Daniel , Werner Nikos , Grube Eberhard , Nickenig Georg , Müller Andreas 
Published: October 2013

Background—
Transcatheter aortic valve implantation (TAVI) is known to be associated with silent cerebral injury, which could contribute to cognitive impairment. Considering its increasing use, thorough longitudinal investigation of cognitive trajectory after TAVI is pivotal.

Methods and Results—

Repeatable battery for the assessment of neuropsychological status was performed before (E1), 3 days (E2), 3 months (E3), 1 (E4) year, and 2 years (E5) after TAVI. Baseline characteristics, procedural data, imaging parameters of brain injury (diffusion-weighted MRI), and the use of conceivable neuroprotective approaches were investigated for their effect on cognitive function. Cognitive performance was investigated in 111 patients (mean log EuroSCORE, 30±13%). Global cognitive function (repeatable battery for the assessment of neuropsychological status total score) increased transiently at E2 (
P
=0.02) and was comparable with baseline levels at E3, E4, and E5. Six patients (5.4%) demonstrated early cognitive decline. Persistence and late onset were seen infrequently (n=3, 2.7% and n=4, 3.6%, respectively). Hence, early cognitive decline was ruled out in 105 patients (94.6%), and a majority of patients (91%) demonstrated sustained cognitive performance throughout all investigated time points. Interestingly, only patient age (
P
=0.012), but not prior cerebrovascular events, cognitive status, direct TAVI, cerebral embolism in diffusion-weighted MRI, or the use of a cerebral embolic protection device was found to be independently associated with cognitive decline, linking higher age to cognitive impairment along the first 2 years after TAVI.

Conclusions—
Long-term cognitive performance was preserved in the great majority (91%) of patients throughout the first 2 years after TAVI, despite the high intrinsic risk for cognitive deterioration.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00883285.
Natural History of Left Ventricular Ejection Fraction in Patients With Heart Failure
Authors: Clarke Christina L. , Grunwald Gary K. , Allen Larry A. , Barón Anna E. , Peterson Pamela N. , Brand David W. , Magid David J. , Masoudi Frederick A. 
Published: October 2013

Background—
Patients with heart failure (HF) are typically designated as having reduced or preserved ejection fraction (HFREF, HFPEF) because of the importance of left ventricular ejection fraction (LVEF) on therapeutic decisions and prognosis. Such designations are not necessarily static, yet few data exist to describe the natural history of LVEF over time.

Methods and Results—
We identified 2413 patients from Kaiser Permanente Colorado with a primary discharge diagnosis of HF between January 1, 2001, and December 31, 2008, who had ≥2 LVEF measurements separated by ≥30 days. We used multi-state Markov modeling to examine transitions among HFREF, HFPEF, and death. We observed a total of 8183 transitions. Women were more likely than men to transition from HFREF to HFPEF (hazard ratio, 1.85; 95% confidence interval, 1.38–2.47). Patients who were adherent to β-blockers were more likely to transition from HFREF to HFPEF (hazard ratio, 1.53; 95% confidence interval, 1.10–2.13) compared with patients who were nonadherent to β-blockers, whereas angiotensin-converting enzyme or angiotensin II receptor blocker adherence was not associated with LVEF transitions. Patients who had a previous myocardial infarction were more likely to transition from HFPEF to HFREF (hazard ratio, 1.75; 95% confidence interval, 1.26–2.42).

Conclusions—
In this cohort of patients with HF, LVEF is a dynamic factor related to sex, coexisting conditions, and drug therapy. These findings have implications for left ventricular systolic function ascertainment in patients with HF and support evidence-based therapy use, especially β-blockers.
Vasculogenesis in Experimental Stroke After Human Cerebral Endothelial Cell Transplantation
Authors: Ishikawa Hiroto , Tajiri Naoki , Shinozuka Kazutaka , Vasconcellos Julie , Kaneko Yuji , Lee Hong J. , Mimura Osamu , Dezawa Mari , Kim Seung U. , Borlongan Cesar V. 
Published: October 2013

Background and Purpose—
Despite the reported functional recovery in transplanted stroke models and patients, the mechanism of action underlying stem cell therapy remains not well understood. Here, we examined the role of stem cell–mediated vascular repair in stroke.

Methods—
Adult rats were exposed to transient occlusion of the middle cerebral artery and 3 hours later randomly stereotaxically transplantated with 100K, 200K, or 400K human cerebral endothelial cell 6 viable cells or vehicle. Animals underwent neurological examination and motor test up to day 7 after transplantation then euthanized for immunostaining against neuronal, vascular, and specific human antigens. A parallel in vitro study cocultured rat primary neuronal cells with human cerebral endothelial cell 6 under oxygen-glucose deprivation and treated with vascular endothelial growth factor (VEGF) and anti-VEGF.

Results—
Stroke animals that received vehicle infusion displayed typical occlusion of the middle cerebral artery–induced behavioral impairments that were dose-dependently reduced in transplanted stroke animals at days 3 and 7 after transplantation and accompanied by increased expression of host neuronal and vascular markers adjacent to the transplanted cells. Some transplanted cells showed a microvascular phenotype and juxtaposed to the host vasculature. Infarct volume in transplanted stroke animals was significantly smaller than vehicle-infused stroke animals. Moreover, rat neurons cocultured with human cerebral endothelial cell 6 or treated with VEGF exhibited significantly less oxygen-glucose deprivation–induced cell death that was blocked by anti-VEGF treatment.

Conclusions—
We found attenuation of behavioral and histological deficits coupled with robust vasculogenesis and neurogenesis in endothelial cell–transplanted stroke animals, suggesting that targeting vascular repair sets in motion a regenerative process in experimental stroke possibly via the VEGF pathway.