bluuebunny/crossref_metadata_2025_split huggingface dataset:
Steroidogenic Germline Polymorphism Predictors of Prostate Cancer Progression in the Estradiol Pathway
Authors: Lévesque Éric , Laverdière Isabelle , Audet-Walsh Étienne , Caron Patrick , Rouleau Mélanie , Fradet Yves , Lacombe Louis , Guillemette Chantal 
Published: March 2014

Abstract
Purpose: Reliable biomarkers that predict prostate cancer outcomes are urgently needed to improve and personalize treatment approaches. With this goal in mind, we individually and collectively appraised common genetic polymorphisms related to estradiol metabolic pathways to find prostate cancer prognostic markers.
Methods: The genetic profiles of 526 men with organ-confined prostate cancer were examined to find common genetic polymorphisms related to estradiol metabolic pathways and these findings were replicated in a cohort of 213 men with more advanced disease (follow-up time for both cohorts, &gt;7.4 years). Specifically, we examined 71 single-nucleotide polymorphisms (SNP) in SULT2A1, SULT2B1, CYP1B1, COMT, CYP3A4, CYP3A5, CYP3A43, NQO1, and NQO2 and assessed the impact of the SNPs alone and in combination on prostate cancer progression and on circulating hormone levels.
Results: According to a multivariate analysis, CYP1B1 (rs1800440), COMT (rs16982844), and SULT2B1 (rs12460535, rs2665582, rs10426628) were significantly associated with prostate cancer progression and hormone levels. Remarkably, by combining the SNP information with previously identified HSD17B2 markers, the patients could be stratified into four distinct prognostic subgroups. The most prominent association was observed for the eight-marker combination [CYP1B1 (rs1800440), SULT2B1 (rs12460535, rs2665582, and rs10426628), and HSD17B2 (rs4243229, rs1364287, rs2955162, and rs1119933)].
Conclusion: This study identified specific germline variations in estradiol metabolism–related pathways, namely CYP1B1, SULT2B1, and HSD17B2, as novel prognostic markers that are cumulatively associated with increased risk of prostate cancer progression. This panel of markers warrants additional investigation and validation to help stratify patients according to their risk of progression. Clin Cancer Res; 20(11); 2971–83. ©2014 AACR.
Leelamine Mediates Cancer Cell Death through Inhibition of Intracellular Cholesterol Transport
Authors: Kuzu Omer F. , Gowda Raghavendra , Sharma Arati , Robertson Gavin P. 
Published: April 2014

Abstract
Leelamine is a promising compound for the treatment of cancer; however, the molecular mechanisms leading to leelamine-mediated cell death have not been identified. This report shows that leelamine is a weakly basic amine with lysosomotropic properties, leading to its accumulation inside acidic organelles such as lysosomes. This accumulation leads to homeostatic imbalance in the lysosomal endosomal cell compartments that disrupts autophagic flux and intracellular cholesterol trafficking as well as receptor-mediated endocytosis. Electron micrographs of leelamine-treated cancer cells displayed accumulation of autophagosomes, membrane whorls, and lipofuscin-like structures, indicating disruption of lysosomal cell compartments. Early in the process, leelamine-mediated killing was a caspase-independent event triggered by cholesterol accumulation, as depletion of cholesterol using β-cyclodextrin treatment attenuated the cell death and restored the subcellular structures identified by electron microscopy. Protein microarray–based analyses of the intracellular signaling cascades showed alterations in RTK–AKT/STAT/MAPK signaling cascades, which was subsequently confirmed by Western blotting. Inhibition of Akt, Erk, and Stat signaling, together with abnormal deregulation of receptor tyrosine kinases, was caused by the inhibition of receptor-mediated endocytosis. This study is the first report demonstrating that leelamine is a lysosomotropic, intracellular cholesterol transport inhibitor with potential chemotherapeutic properties leading to inhibition of autophagic flux and induction of cholesterol accumulation in lysosomal/endosomal cell compartments. Importantly, the findings of this study show the potential of leelamine to disrupt cholesterol homeostasis for treatment of advanced-stage cancers. Mol Cancer Ther; 13(7); 1690–703. ©2014 AACR.
The Tumor Microenvironment Shapes Lineage, Transcriptional, and Functional Diversity of Infiltrating Myeloid Cells
Authors: Elpek Kutlu G. , Cremasco Viviana , Shen Hua , Harvey Christopher J. , Wucherpfennig Kai W. , Goldstein Daniel R. , Monach Paul A. , Turley Shannon J. 
Published: April 2014

Abstract
Myeloid cells play important regulatory roles within the tumor environment by directly promoting tumor progression and modulating the function of tumor-infiltrating lymphocytes, and as such, they represent a potential therapeutic target for the treatment of cancer. Although distinct subsets of tumor-associated myeloid cells have been identified, a broader analysis of the complete myeloid cell landscape within individual tumors and also across different tumor types has been lacking. By establishing the developmental and transcriptomic signatures of infiltrating myeloid cells from multiple primary tumors, we found that tumor-associated macrophages (TAM) and tumor-associated neutrophils (TAN), while present within all tumors analyzed, exhibited strikingly different frequencies, gene expression profiles, and functions across cancer types. We also evaluated the impact of anatomic location and circulating factors on the myeloid cell composition of tumors. The makeup of the myeloid compartment was determined by the tumor microenvironment rather than the anatomic location of tumor development or tumor-derived circulating factors. Protumorigenic and hypoxia-associated genes were enriched in TAMs and TANs compared with splenic myeloid-derived suppressor cells. Although all TANs had an altered expression pattern of secretory effector molecules, in each tumor type they exhibited a unique cytokine, chemokine, and associated receptor expression profile. One such molecule, haptoglobin, was uniquely expressed by 4T1 TANs and identified as a possible diagnostic biomarker for tumors characterized by the accumulation of myeloid cells. Thus, we have identified considerable cancer-specific diversity in the lineage, gene expression, and function of tumor-infiltrating myeloid cells. Cancer Immunol Res; 2(7); 655–67. ©2014 AACR.
Targeting Immune Suppression with PDE5 Inhibition in End-Stage Multiple Myeloma
Authors: Noonan Kimberly A. , Ghosh Nilanjan , Rudraraju Lakshmi , Bui Marilyn , Borrello Ivan 
Published: March 2014

AbstractMyeloid-derived suppressor cells (MDSC) play a significant role in tumor-induced immune suppression. Targeting their function could improve antitumor therapies. Previously, we demonstrated that phosphodiesterase 5 (PDE5) inhibition in MDSCs augmented antitumor immunity in murine models. Here, we show how the addition of the PDE5 inhibitor, tadalafil, in a patient with end-stage relapsed/refractory multiple myeloma reduced MDSC function and generated a dramatic and durable antimyeloma immune and clinical response. Strategies targeting MDSC function with PDE5 inhibitors represent a novel approach that can augment the efficacy of tumor-directed therapies. Cancer Immunol Res; 2(8); 725–31. ©2014 AACR.
Feasibility and cost-effectiveness of stroke prevention through community screening for atrial fibrillation using iPhone ECG in pharmacies
Authors: Lowres Nicole , Neubeck Lis , Salkeld Glenn , Krass Ines , McLachlan Andrew J. , Redfern Julie , Bennett Alexandra A. , Briffa Tom , Bauman Adrian , Martinez Carlos , Wallenhorst Christopher , Lau Jerrett K. , Brieger David B. , Sy Raymond W. , Freedman S. Ben 
Published: April 2014

SummaryAtrial fibrillation (AF) causes a third of all strokes, but often goes undetected before stroke. Identification of unknown AF in the community and subsequent anti-thrombotic treatment could reduce stroke burden. We investigated community screening for unknown AF using an iPhone electrocardiogram (iECG) in pharmacies, and determined the cost-effectiveness of this strategy. Pharmacists performed pulse palpation and iECG recordings, with cardiologist iECG over-reading. General practitioner review/12-lead ECG was facilitated for suspected new AF. An automated AF algorithm was retrospectively applied to collected iECGs. Cost-effectiveness analysis incorporated costs of iECG screening, and treatment/outcome data from a United Kingdom cohort of 5,555 patients with incidentally detected asymptomatic AF. A total of 1,000 pharmacy customers aged ≥65 years (mean 76 ± 7 years; 44% male) were screened. Newly identified AF was found in 1.5% (95% CI, 0.8–2.5%); mean age 79 ± 6 years; all had CHA2DS2-VASc score ≥2. AF prevalence was 6.7% (67/1,000). The automated iECG algorithm showed 98.5% (CI, 92–100%) sensitivity for AF detection and 91.4% (CI, 89–93%) specificity. The incremental cost-effectiveness ratio of extending iECG screening into the community, based on 55% warfarin prescription adherence, would be $AUD5,988 (€3,142; $USD4,066) per Quality Adjusted Life Year gained and $AUD30,481 (€15,993; $USD20,695) for preventing one stroke. Sensitivity analysis indicated cost-effectiveness improved with increased treatment adherence. Screening with iECG in pharmacies with an automated algorithm is both feasible and cost-effective. The high and largely preventable stroke/thromboembolism risk of those with newly identified AF highlights the likely benefits of community AF screening. Guideline recommendation of community iECG AF screening should be considered.Previous Presentation: This study was presented in part as an oral presentation at the Cardiac Society of Australia and New Zealand Conference; 9 August 2013; Sydney, Australia, abstract published in Heart Lung Circulation 2013;22:S223.Trial registration: Australian New Zealand clinical trials registry: ACTRN12612000406808.
Mesenchymal Precursor Cells as Adjunctive Therapy in Recipients of Contemporary Left Ventricular Assist Devices
Authors: Ascheim Deborah D. , Gelijns Annetine C. , Goldstein Daniel , Moye Lemuel A. , Smedira Nicholas , Lee Sangjin , Klodell Charles T. , Szady Anita , Parides Michael K. , Jeffries Neal O. , Skerrett Donna , Taylor Doris A. , Rame J. Eduardo , Milano Carmelo , Rogers Joseph G. , Lynch Janine , Dewey Todd , Eichhorn Eric , Sun Benjamin , Feldman David , Simari Robert , O’Gara Patrick T. , Taddei-Peters Wendy C. , Miller Marissa A. , Naka Yoshifumi , Bagiella Emilia , Rose Eric A. , Woo Y. Joseph 
Published: March 2014

Background—
Allogeneic mesenchymal precursor cells (MPCs) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy.

Methods and Results—

In this multicenter, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25 million MPCs or medium during LVAD implantation. The primary safety end point was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days after randomization). Key efficacy end points were functional status and ventricular function while temporarily weaned from LVAD support (90 days after randomization). Patients were followed up until transplant or 12 months after randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean left ventricular ejection fraction was 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (
P
=0.24); the posterior probability that MPCs increased the likelihood of successful weaning was 93%. At 90 days, 3 deaths (30%) occurred in control patients, and none occurred in MPC patients. Mean left ventricular ejection fraction after successful wean was 24.0% (MPC=10) and 22.5% (control=2;
P
=0.56). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support (
P
=0.69), and 6 deaths (30%) occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months.

Conclusions—
In this preliminary trial, administration of MPCs appeared to be safe, and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01442129.
Time of Society and Time of Experience: Multiple Times and Social Change
Authors: Leccardi Carmen 
Published: March 2014

AbstractJ. T. Fraser highlighted the distinctive connections between the different levels of temporality that characterize the human timescape. In this context, he also demonstrated a clear awareness of the relationship between sociotemporality and the existential processing of time. Human experience, in its myriad expressions, bears the mark of the social processes and dynamics within which it takes shape. Analyzing this relationship, we can assert that identity itself is marked by the conception of time that characterizes a given historical period. Processes of social change, forms of experience, identities and expressions of subjectivity are therefore interwoven. The ways in which we experience and conceive of time should therefore also be interpreted in the light of this interconnection. In this particular period, information technologies appear to have the power to redefine the whole of human experience, including our experience of time. After analyzing the close relationship between time and identity, and the multiplicity of temporal dimensions it comprises, referencing social phenomenology, the paper explores the nature of the processes of change that characterize our era—starting from the crisis of the future and the dynamics connected to the acceleration of time. The general aim is to highlight the link between historical times, social times and individual times. It looks at the reflection formulated by J. T. Fraser on the multiplicity of times as it relates to the analytical tools developed by the sociology of time.
The Protestant Israelites of Sancerre: Jean de Léry and the Confessional Demarcation of Cannibalism
Authors: Duker Adam Asher 
Published: March 2014

Abstract
This article explores how Jean de Léry understood Protestant, Catholic, and Brazilian acts of cannibalism. It argues that Léry constructed a new Huguenot confessional identity in the wake of the Saint Bartholomew’s Day Massacre by equating his own besieged community in Sancerre with the anthropophagous Israelites of the Hebrew Bible. He counts his own people as the worst of all cannibals, for like the ancient Israelites, the Huguenots of Sancerre possessed a superior understanding of God’s will but ate each other nonetheless. Léry makes these judgments by invoking examples of man-eating from the Bible and Josephus, as well as contemporary acts of cannibalism. His identification of the Huguenots with unfaithful Israel represents a break from the more optimistic conceptions of Israelite identity held by Jean Crespin and others prior to the St. Bartholomew’s Day Massacre. By equating the inhabitants of Sancerre with the cannibals of ancient Israel, Léry extends John Calvin’s sacramental reasoning concerning the linguistic relationship between the sign and the thing signified far beyond its original scope. He does this in order to come to grips with the new reality that the Huguenots, whose fortunes were ascending prior to the Massacre, were now witnessing a decidedly dark turn in what they perceived to be God’s providence.
Law and the Exclusionary Essence of Large-Scale Investments in Sub-Saharan Africa Land
Authors: Ferrando Tomaso 
Published: March 2014

Abstract
‘Global land grabbing’ represents one of the hottest topics of debate within the areas of developmental and agricultural studies. However, this article claims that a narrow focus on the illegality and consequences of the ‘grabbing’, rather than on large scale investments in land (LaSIL) as a form of economic development which is inherently exclusionary, can be detrimental to the future of small-scale farmers. A short-term perspective overlooks the indirect consequences of industrialization, and legitimizes long-term exclusions and marginalization. Through past and present evidence, this paper demonstrates that LaSIL as competing projects will inevitably produce the abandonment of rural areas, the proletarianization of peasants, and the increase in social inequality, against any possibility for coexistence and harmonious cooperation.
Integrated Water Resource Management, Public Participation and the ‘Rainbow Nation’
Authors: Razzaque Jona , Kleingeld Eloise S. 
Published: March 2014

Abstract
This article provides varied examples of Integrated Water Resource Management (IWRM) and public participation interaction in South Africa. It critically examines the inadequate application of IWRM, and shows how the unbalanced interpretations of IWRM as well as a lack of good development practice and participatory rights manifest in negative outcomes for the poorest and most vulnerable. This paper, first, highlights that if decision-makers are primarily fixed on economic concerns, they induce inefficient IWRM framework that fails to balance water as a social, economic and ecological concern. Second: when the state fails to consult people and violate human and environmental rights, court battles ensue between the state and the people. These court cases are generally expensive for both sides and marred with delay. Third: positive outcomes can be attained through multi-stakeholder dialogue platforms which can operate as a sort of conflict resolution mechanism encompassing divergent views, but still offering beneficial outcomes. The frameworks and practical examples set by the Water Dialogues South Africa can facilitate public participation and capacity building if applied at local levels by decision-makers. IWRM with public participation at its heart engenders an ultimate objective for better water sustainability and water security in South Africa.
From Durable Solutions to Holistic Solutions: Prevention of Displacement in Africa
Authors: Kuwali Dan 
Published: March 2014

Abstract
The problem of internally displaced persons (IDPs) is prevalent in Africa due to conflicts, development projects, man-made as well as natural disasters that are commonplace on the continent. The Kampala Convention, which is an innovative tool, seeks to provide African States with a roadmap towards long-term solutions to prevent and eradicate the causes of displacement. As such, African States, humanitarian agencies, the African Union and other stakeholders should go beyond durable solutions, which are reactive, and pay more attention to proactive strategies to eradicate the factors that lead to displacement. To do this, there is need to adopt a holistic approach to address the question of IDPs on the continent through a three-tiered strategy that includes; firstly, short-term strategy to protect the IDPs by providing safety and security, freedom of movement as well as basic livelihood to the IDPs; secondly, medium-term strategy to restore IDPs’ dignity and ensure adequate living conditions through return, resettlement, (re)integration, reparation, restitution and rehabilitation; and thirdly, long-term strategy to eradicate root causes of displacement and fostering an environment conducive to respect of human rights, rule of law and good governance.
Emerging Trends and the General Framework for the Exercise of Sentencing Discretion in Botswana
Authors: Malila Ikanyeng S. 
Published: March 2014

Abstract
Like other common law jurisdictions, Botswana has, in recent years, seen an increase in the number of interventions by the legislature to structure sentencing powers of judges through primary legislation. This trend has given rise to concerns about the erosion of the sentencing discretion of judges in some quarters. Against this background the present paper outlines and discusses the nature of discretion exercisable by judges in sentencing matters in Botswana and the general framework for the exercise of such powers. The paper argues that despite the recent increase in the volume of mandatory minimum enactments, the general framework for the exercise of discretion in Botswana remains fundamentally unchanged not least because the courts have in some measure reclaimed some of the discretion they had lost as a result of unprecedented expansion in the volume of mandatory minimum legislation in the 1990s. More positively, a recent amendment to the Penal Code restoring some of the judges’ discretion suggests that parliament has come to recognise the need for and importance of greater flexibility in the structure of the sentencing discretion of judges.
Pharmaceutical Patents in Developing Nations: Parallel Importation and the Doctrine of Exhaustion
Authors: McKeith Sarah 
Published: March 2014

Abstract
This article examines the impact of parallel importation and the doctrine of patent exhaustion on access to pharmaceutical products in developing nations around the world. Parallel importation is of particular relevance to developing countries given that it is in these countries where medicines are often limited and exorbitant prices can be charged for those drugs that are available. Against this backdrop, this article examines the international legal regulation of patent exhaustion and proposes a solution to the difficulties currently experienced by many developing countries in attempting to use parallel importation to promote public health and improve access to medicines. The solution proposed in this article comprises a regional approach to patent exhaustion, which involves the introduction of complimentary legal and policy measures to the regional framework that currently exists in the developing world. It is argued that this proposal strikes an optimal balance between protecting intellectual property rights and increasing access to medicines that works in the best interests of pharmaceutical patent holders and developing country patent users.
Statelessness and Rights: Protecting the Rights of Nubian Children in Kenya through the African Children’s Committee
Authors: Fokala Elvis , Chenwi Lilian 
Published: March 2014

Abstract
The question of statelessness is an incessant challenge in Africa. Stateless persons are often denied basic human rights due to lack of a nationality. The situation of children in Kenya – that are of Nubian descent – is illustrative of the plight faced by stateless persons. The African Committee of Experts on the Rights and Welfare of the Child has attempted to address this challenge in its first decision, made public in 2011. This article considers this decision, analysing its strengths and weaknesses as well as the potential impact of the decision.