bluuebunny/crossref_metadata_2025_split huggingface dataset:
Falls in Older people with Cataract, a longitudinal evalUation of impact and riSk: the FOCUS study protocol
Authors: Keay Lisa , Palagyi Anna , McCluskey Peter , Lamoureux Ecosse , Pesudovs Konrad , Lo Serigne , Ivers Rebecca , Boufous Soufiane , Morlet Nigel , Ng Jonathon Q , Stapleton Fiona , Fraser Michelle , Meuleners Lynn 
Published: January 2014

BackgroundFalls result in >$1 billion in treatment, disability, lost output and mortality each year in Australia and people with cataract are at increased risk. Previous research is inconclusive; one large Australian study using linked hospital data found no protective effect of cataract surgery. We aim to examine the impact of cataract-related vision impairment on falls risk and the additional effects of delays in access to surgery, refractive management (type of spectacles and changes to spectacle prescription) and the resulting level of function, particularly binocular function which can impact balance.Method/designA prospective, 24-month cohort study is planned involving over 700 patients aged 70 years or older with bilateral cataract presenting for surgery at five public hospital eye clinics in Sydney, Melbourne and Perth, Australia. The primary outcomes will be self-reported falls and falls requiring medical care, assessed objectively using administrative data sets. Secondary outcomes include community participation, quality of life, mood and depressive symptoms. McNemar's test will be used to evaluate differences in falls rate before, after first eye and after second eye cataract surgery. Generalised Estimating Equations linear regression analysis will be undertaken to examine factors associated with falls risk and the secondary outcomes.DiscussionWith limited resources to further shorten public waiting lists, there is a need to better understand an individuals’ risk of fall injury or other negative consequences while waiting for surgery. The findings of this project will inform the development of strategies to reduce falls risk in the many older people with cataract.
A qualitative study of the use of the four quadrant approach to assist ethical decision-making during deployment
Authors: Bernthal Elizabeth M M , Russell R J , Draper H J A 
Published: January 2014

AimThe aim of the study was to explore how useful clinicians deployed to the Field Hospital in Afghanistan found using the four quadrant approach (4QA) as a tool to aid ethical decision-making. In addition, the study aimed to determine whether the 4QA needed to be amended to make it more effective in assisting the ethical decision-making process for military health professionals on deployment.MethodA qualitative pilot study in two phases was undertaken between September 2012 and January 2013. In Phase I, senior deployed clinicians completed a pro forma of the 4QA on cases that potentially raised ethical issues. Thirteen pro formas were submitted on four cases; the Deployed Medical Director submitted a log of 14 cases that had involved using the 4QA. Phase II consisted of interviews with five senior clinicians who had recently returned from deployment in Afghanistan to discuss their experiences and perceptions of using the 4QA.ResultsPhase I identified a variation in the level of detail recorded and where that information was placed on the quadrant. Four themes were generated from Phase II. These included the characteristics of ethical decisions; the processes used to make ethical decisions; use, usefulness and limitations of the 4QA; and views about training in ethics. The findings suggested that amendments to the pro forma may improve its utility.ConclusionsThe 4QA is a useful tool within an operational setting but amending its diagrammatic presentation could improve its effectiveness. Pre-deployment training should include practising using the quadrant as described inClinical Guidelines for Operations. This is particularly important as the participants relied heavily on experience to help them make ethical decisions, and this experience may not be available in future operations outside Afghanistan.
P5-FACTORIZATION OF CARTESIAN PRODUCT OF GRAPHS
Authors: TAMIL ELAKKIYA A. , MUTHUSAMY A. 
Published: January 2014

Partition of G into edge-disjoint H-factors is called H-factorization of G. Muthusamy and Paulraja have conjectured that for k ≥ 3, Km□Kn has a Pk-factorization if and only if mn ≡ 0 ( mod k) and k(m + n - 2) ≡ 0 ( mod 2(k - 1)), where □ denote cartesian product of graphs. In this paper, it is shown that the necessary conditions mn ≡ 0 ( mod 5) and 5(m + 1) ≡ 0 ( mod 8) are sufficient for the existence of a P5-factorization of Km□Cn when (i) m = 7, n ≡ 0 ( mod 5), (ii) m ≡ 175 ( mod 280), n ≡ 0( mod 5). Further, it is shown that the necessary conditions mn ≡ 0 ( mod 5) and 5(m + n - 2) ≡ 0 ( mod 8) are sufficient for the existence of a P5-factorization of Km□Kn in the following cases: (i) m ≡ 5 ( mod 40), n ≡ 5 ( mod 40), (ii) m ≡ 10 ( mod 40), n ≡ 0 ( mod 40), (iii) m ≡ 15 ( mod 120), n = 3 and m ≡ 15 ( mod 120), n ≡ 75 ( mod 120), (iv) m ≡ 20 ( mod 40), n ≡ 30 ( mod 120), (v) m ≡ 25 ( mod 40), n ≡ 25 ( mod 40), (vi) m ≡ 30 ( mod 120), n = 4 and m ≡ 30 ( mod 120), n ≡ 20 ( mod 40), (vii) m ≡ 75 ( mod 120), n ≡ 15 ( mod 120), (viii) m ≡ 0 ( mod 40), n = 2 and m ≡ 0 ( mod 40), n ≡ 10 ( mod 40). In fact our results partially answer the above conjecture when k = 5.
CD133+ Cancer Stem-like Cells in Small Cell Lung Cancer Are Highly Tumorigenic and Chemoresistant but Sensitive to a Novel Neuropeptide Antagonist
Authors: Sarvi Sana , Mackinnon Alison C. , Avlonitis Nicolaos , Bradley Mark , Rintoul Robert C. , Rassl Doris M. , Wang Wei , Forbes Stuart J. , Gregory Christopher D. , Sethi Tariq 
Published: January 2014

AbstractSmall cell lung cancer (SCLC) is a highly aggressive malignancy with poor survival rates, with initial responses nearly invariably followed by rapid recurrence of therapy-resistant disease. Drug resistance in SCLC may be attributable to the persistence of a subpopulation of cancer stem-like cells (CSC) that exhibit multiple drug resistance. In this study, we characterized the expression of CD133, one important marker of CSC in other cancers, in SCLC cancer cells. CD133 expression correlated with chemoresistance and increased tumorigenicity in vitro and in vivo accompanied by increased expression of Akt/PKB and Bcl-2. CD133 expression was increased in mouse and human SCLC after chemotherapy, an observation confirmed in clinical specimens isolated longitudinally from a patient receiving chemotherapy. We discovered in CD133+ SCLC cells, an increased expression of the mitogenic neuropeptide receptors for gastrin-releasing peptide and arginine vasopressin. Notably, these cells exhibited increased sensitivity to the growth inhibitory and proapoptotic effects of a novel broad spectrum neuropeptide antagonist (related to SP-G), which has completed a phase I clinical trial for SCLC. Our results offer evidence that this agent can preferentially target chemoresistant CD133+ cells with CSC character in SCLC, emphasizing its potential utility for improving therapy in this setting. Cancer Res; 74(5); 1554–65. ©2014 AACR.
Suppression of MicroRNA-9 by Mutant EGFR Signaling Upregulates FOXP1 to Enhance Glioblastoma Tumorigenicity
Authors: Gomez German G. , Volinia Stefano , Croce Carlo M. , Zanca Ciro , Li Ming , Emnett Ryan , Gutmann David H. , Brennan Cameron W. , Furnari Frank B. , Cavenee Webster K. 
Published: January 2014

Abstract
The EGF receptor (EGFR) is amplified and mutated in glioblastoma, in which its common mutation (ΔEGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that ΔEGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs might serve such a function. Here, we report that ΔEGFR specifically suppresses one such microRNA, namely miR-9, through the Ras/PI3K/AKT axis that it is known to activate. Correspondingly, expression of miR-9 antagonizes the tumor growth advantage conferred by ΔEGFR. Silencing of FOXP1, a miR-9 target, inhibits ΔEGFR-dependent tumor growth and, conversely, de-repression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic ΔEGFR signaling. The significance of these findings is underscored by our finding that high FOXP1 expression predicts poor survival in a cohort of 131 patients with glioblastoma. Collectively, these data suggest a novel regulatory mechanism by which ΔEGFR suppression of miR-9 upregulates FOXP1 to increase tumorigenicity. Cancer Res; 74(5); 1429–39. ©2014 AACR.
A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Panobinostat, an HDAC Inhibitor, Combined with Erlotinib in Patients with Advanced Aerodigestive Tract Tumors
Authors: Gray Jhanelle E. , Haura Eric , Chiappori Alberto , Tanvetyanon Tawee , Williams Charles C. , Pinder-Schenck Mary , Kish Julie A. , Kreahling Jenny , Lush Richard , Neuger Anthony , Tetteh Leticia , Akar Angela , Zhao Xiuhua , Schell Michael J. , Bepler Gerold , Altiok Soner 
Published: January 2014

Abstract
Purpose: Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non–small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer.
Experimental Design: Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed.
Results: Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1–3), and rash and anorexia (grades 1–2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02).
Conclusions: We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role. Clin Cancer Res; 20(6); 1644–55. ©2014 AACR.
Genetic and Pharmacologic Evidence That mTOR Targeting Outweighs mTORC1 Inhibition as an Antimyeloma Strategy
Authors: Chen Xi , Díaz-Rodríguez Elena , Ocio Enrique M. , Paiva Bruno , Mortensen Deborah S. , Lopez-Girona Antonia , Chopra Rajesh , Miguel Jesús San , Pandiella Atanasio 
Published: January 2014

Abstract
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, proliferation, metabolism, and cell survival, and plays those roles by forming two functionally distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Deregulation of the mTOR pathway has been found in different cancers, including multiple myeloma. Agents acting on mTORC1, such as rapamycin and derivatives, are being explored as antitumoral strategies. However, whether targeting mTOR would be a more effective antimyeloma strategy than exclusively acting on the mTORC1 branch remains to be established. In this report, we explored the activation status of mTOR routes in malignant plasma cells, and analyzed the contribution of mTOR and its two signaling branches to the proliferation of myeloma cells. Gene expression profiling demonstrated deregulation of mTOR pathway–related genes in myeloma plasma cells from patients. Activation of the mTOR pathway in myelomatous plasma cells was corroborated by flow cytometric analyses. RNA interference (RNAi) experiments indicated that mTORC1 predominated over mTORC2 in the control of myeloma cell proliferation. However, mTOR knockdown had a superior antiproliferative effect than acting only on mTORC1 or mTORC2. Pharmacologic studies corroborated that the neutralization of mTOR has a stronger antimyeloma effect than the individual inhibition of mTORC1 or mTORC2. Together, our data support the clinical development of agents that widely target mTOR, instead of agents, such as rapamycin or its derivatives, that solely act on mTORC1. Mol Cancer Ther; 13(2); 504–16. ©2014 AACR.
Mutant Ras Elevates Dependence on Serum Lipids and Creates a Synthetic Lethality for Rapamycin
Authors: Salloum Darin , Mukhopadhyay Suman , Tung Kaity , Polonetskaya Aleksandra , Foster David A. 
Published: January 2014

Abstract
The conversion of normal cells to cancer cells involves a shift from catabolic to anabolic metabolism involving increased glucose uptake and the diversion of glycolytic intermediates into nucleotides, amino acids, and lipids needed for cell growth. An underappreciated aspect of nutrient uptake is the utilization of serum lipids. We investigated the dependence of human cancer cells on serum lipids and report here that Ras-driven human cancer cells are uniquely dependent on serum lipids for both proliferation and survival. Removal of serum lipids also sensitizes Ras-driven cancer cells to rapamycin—indicating that the enhanced need for serum lipids creates a synthetic lethal phenotype that could be exploited therapeutically. Although depriving humans of serum lipids is not practical, suppressing uptake of lipids is possible. Suppressing macropinocytosis in Ras-driven cancer cells also created sensitivity to suppression of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). It is speculated that this property displayed by Ras-driven cancer cells represents an Achilles' heel for the large number of human cancers that are driven by activating Ras mutations. Mol Cancer Ther; 13(3); 733–41. ©2014 AACR.
Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution
Authors: Dewhurst Sally M. , McGranahan Nicholas , Burrell Rebecca A. , Rowan Andrew J. , Grönroos Eva , Endesfelder David , Joshi Tejal , Mouradov Dmitri , Gibbs Peter , Ward Robyn L. , Hawkins Nicholas J. , Szallasi Zoltan , Sieber Oliver M. , Swanton Charles 
Published: January 2014

Abstract
The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows chromosome abnormalities to evolve specifically in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early-stage disease in two independent cohorts in multivariate analyses [discovery data: hazard ratio (HR), 4.70, 95% confidence interval (CI), 1.04–21.37; validation data: HR, 1.59, 95% CI, 1.05–2.42]. These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution.
Significance: Our work sheds light on the importance of whole-genome–doubling events in colorectal cancer evolution. We show that tetraploid cells undergo rapid genomic changes and recapitulate the genetic alterations seen in chromosomally unstable tumors. Furthermore, we demonstrate that a genome-doubling event is prognostic of poor relapse-free survival in this disease type. Cancer Discov; 4(2); 175–85. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 131
A novel approach to assess the spontaneous gastrointestinal bleeding risk of antithrombotic agents using Apc
min/+ mice
Authors: Wei Huijun , Shang Jin , Keohane CarolAnn , Wang Min , Li Qiu , Ni Weihua , O’Neill Kim , Chintala Madhu 
Published: January 2014

SummaryAssessment of the bleeding risk of antithrombotic agents is usually performed in healthy animals with some form of vascular injury to peripheral organs to induce bleeding. However, bleeding observed in patients with currently marketed antithrombotic drugs is typically spontaneous in nature such as intracranial haemorrhage (ICH) and gastrointestinal (GI) bleeding, which happens most frequently on top of preexisting pathologies such as GI ulcerations and polyps. Apc
min/+ mice are reported to develop multiple adenomas through the entire intestinal tract and display progressive anaemia. In this study, we evaluated the potential utility of Apc
min/+ mice as a model for assessing spontaneous GI bleeding with antithrombotic agents. Apc
min/+ mice exhibited progressive blood loss starting at the age of nine weeks. Despite the increase in bleeding, Apc
min/+ mice were in a hypercoagulable state and displayed an age-dependent increase in thrombin generation and circulating fibrinogen as well as a significant decrease in clotting times. We evaluated the effect of warfarin, dabigatran etexilate, apixaban and clopidogrel in this model by administering them in diet or in the drinking water to mice for 1–4 weeks. All of these marketed drugs significantly increased GI bleeding in Apc
min/+ mice, but not in wild-type mice. Although different exposure profiles of these antithrombotic agents make it challenging to compare the bleeding risk of compounds, our results indicate that the Apc
min/+ mouse may be a sensitive preclinical model for assessing the spontaneous GI bleeding risk of novel antithrombotic agents.
Ribosomal Protein L13a Deficiency in Macrophages Promotes Atherosclerosis by Limiting Translation Control-Dependent Retardation of Inflammation
Authors: Basu Abhijit , Poddar Darshana , Robinet Peggy , Smith Jonathan D. , Febbraio Maria , Baldwin William M. , Mazumder Barsanjit 
Published: January 2014

Objective—
Unresolved inflammatory response of macrophages plays a pivotal role in the pathogenesis of atherosclerosis. Previously we showed that ribosomal protein L13a-dependent translational silencing suppresses the synthesis of a cohort of inflammatory proteins in monocytes and macrophages. We also found that genetic abrogation of L13a expression in macrophages significantly compromised the resolution of inflammation in a mouse model of lipopolysaccharide-induced endotoxemia. However, its function in the pathogenesis of atherosclerosis is not known. Here, we examine whether L13a in macrophage has a protective role against high-fat diet–induced atherosclerosis.

Approach and Results—

We bred the macrophage-specific L13a knockout mice L13a Flox
+/+
Cre
+/+
onto apolipoprotein E–deficient background and generated the experimental double knockout mice L13a Flox
+/+
Cre
+/+
apolipoprotein E deficient (apoE
−/−
). L13a Flox
+/+
Cre
−/−
mice on apolipoprotein E–deficient background were used as controls. Control and knockout mice were subjected to high-fat diet for 10 weeks. Evaluation of aortic sinus sections and entire aorta by en face showed significantly higher atherosclerosis in the knockout mice. Severity of atherosclerosis in knockout mice was accompanied by thinning of the smooth muscle cell layer in the media, larger macrophage area in the intimal plaque region and higher plasma levels of inflammatory cytokines. In addition, macrophages isolated from knockout mice had higher polyribosomal abundance of several target mRNAs, thus showing defect in translation control.

Conclusions—
Our data demonstrate that loss of L13a in macrophages increases susceptibility to atherosclerosis in apolipoprotein E–deficient mice, revealing an important role of L13a-dependent translational control as an endogenous protection mechanism against atherosclerosis.
Subclinical Atherosclerosis in Systemic Lupus Erythematosus and Antiphospholipid Syndrome
Authors: Conti Fabrizio , Spinelli Francesca Romana , Alessandri Cristiano , Pacelli Massimo , Ceccarelli Fulvia , Marocchi Elisa , Montali Anna , Capozzi Antonella , Buttari Brigitta , Profumo Elisabetta , Sorice Maurizio , Arca Marcello , Valesini Guido , Riganò Rachele 
Published: January 2014

Objective—
Systemic Lupus Erythematosus (SLE) and antiphospholipid syndrome (APS) are associated with a high prevalence of atherosclerosis. β2 glycoprotein I (β2GPI) represents a link between autoimmunity and endothelial dysfunction. Recently, β2GPI reactive T cells have been identified; however, their role in atherosclerosis is still under investigation. We evaluated early atherosclerosis in patients with SLE and APS and investigated T cell reactivity to β2GPI and its relationship with atherosclerotic process.

Approach and Results—

Fifty SLE, 18 patients with primary APS (PAPS), and 25 healthy controls were enrolled. Demographic and clinical data, including traditional cardiovascular risk factors, were recorded. Monocyte β2GPI and Tissue Factor (TF) expression and peripheral blood mononuclear cell response to β2GPI stimulation were evaluated. Doppler ultrasound was performed to investigate flow-mediated dilatation (FMD) and carotid intima-media thickness (IMT). We detected an increase in mean IMT and a decrease in FMD in patients with SLE versus controls (
P
<0.05 and
P
=0.0001, respectively) and a decrease in FMD in patients with PAPS versus controls (
P
<0.05). Monocyte β2GPI and TF expression was higher in patients with SLE and PAPS than in controls (
P
=0.006 and
P
=0.001, respectively); no correlation of monocyte β2GPI and TF with IMT or FMD was detected. β2GPI induced peripheral blood mononuclear cell proliferation in 32% of patients with SLE, 25% of patients with PAPS yet in none of the controls. Proliferative response to β2GPI correlated with a history of arterial thrombosis, thrombocytopenia, and IMT >0.9 mm.

Conclusions—
A significant percentage of patients with SLE and PAPS show a β2GPI-specific T cell reactivity, which is associated with subclinical atherosclerosis.
Two new tardigrade species from Sicily
Authors: PILATO GIOVANNI , SABELLA GIORGIO , LISI OSCAR 
Published: January 2014

Two new species of tardigrades are described from Sicilian moss samples: Macrobiotus insuetus sp. nov. and Diphascon (Diphascon) procerum sp. nov. Macrobiotus insuetus sp. nov. is a species of the harmsworthi-group characterized by both posterior and anterior claws of the hind legs, which are different in shape from those of the first three leg pairs. The IV claws have extended basal tract where the branches are joined and the secondary branch breaks at near right angle to the primary branch and is clearly shorter than the main branch and the secondary branch of claws I-III. The eggs are not areolated and have conical processes with a reticular ornamentation. Diphascon (D.) procerum sp. nov. has a delicate cuticular ornamentation of very small tubercles, almost dots; two macroplacoids and septulum are present; thin accessory points are present on the main branches of the slender claws; lunules are absent but the base of the external claws of the hind legs are enlarged and slightly indented; a cuticular bar is present near the internal claw of the first three leg pairs and two cuticular bars are present on the hind legs between the base of the claws and near the base of the anterior claw.