bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opportunity Nox: The Future of NADPH Oxidases as Therapeutic Targets in Cardiovascular Disease
Authors: Streeter Jennifer , Thiel William , Brieger Kate , Miller, Jr. Francis J. 
Published: January 2012

SummaryOver 40 years ago, NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 2 (Nox2) was discovered in phagocytes and found to be essential in innate immunity. More than 20 years passed before additional Nox isoforms were discovered; and since then, studies have revealed that several of these isoforms (Nox1, Nox2, Nox4, and Nox5) are found in human cardiac and vascular cells and contribute to the pathogenesis of cardiovascular diseases (CVDs). Recently, major efforts have focused on identifying inhibitors capable of ameliorating Nox‐mediated CVD. In this review, we briefly discuss the role of each Nox isoform in CVD, identify steps in Nox signaling that will serve as potential targets for the design of therapeutics, and highlight innovative strategies likely to yield effective Nox inhibitors within the next decade.
The United Nations and Human Development: From Ideology to Global Policies
Authors: Thérien Jean‐Philippe 
Published: January 2012

AbstractBuilding on the work of the United Nations Intellectual History Project, this article argues that the ideology of human development has now become the driving normative force behind the global policies supported by the UN in the area of development. The first part focuses on the UN’s official discourse of the past two decades, and shows how it has been influenced by the concept of human development. The second section examines a set of global policies that illustrate how the UN has sought to put the principles of human development into practice. The article concludes that while human development ideology has represented for twenty years the most credible critique of mainstream development policies, its impact – like that of the UN in world affairs – remains nonetheless limited.Policy Implications
Human development currently represents the most credible alternative to mainstream development thinking and the most effective approach to fostering global justice.
The UN must provide greater leadership in showing that the future of global order will depend on the future of human development.
The UN should be far more pro‐active in identifying and fighting against the national and international factors that impede human development.
The coherence of global policies affecting human development needs to be strengthened.
The UN must cooperate much more closely with like‐minded social forces to effectually promote human development.
Validation of a new point‐of‐care assay for determination of β‐carotene concentration in bovine whole blood and plasma
Authors: Raila Jens , Enjalbert Francis , Mothes Ralf , Hurtienne Andrea , Schweigert Florian J. 
Published: January 2012

Backgroundβ‐Carotene is an important precursor of vitamin A, and is associated with bovine fertility. β‐Carotene concentrations in plasma are used to optimize β‐carotene supplementation in cattle, but measurement requires specialized equipment to separate plasma and extract and measure β‐carotene, either using spectrophotometry or high performance liquid chromatography (HPLC).ObjectiveThe objective of this study was to validate a new 2‐step point‐of‐care (POC) assay for measuring β‐carotene in whole blood and plasma.Methodsβ‐carotene concentrations in plasma from 166 cows were measured using HPLC and compared with results obtained using a POC assay, the iCheck‐iEx‐Carotene test kit. Whole blood samples from 23 of these cattle were also evaluated using the POC assay and compared with HPLC‐plasma results from the same 23 animals. The POC assay includes an extraction vial (iEx Carotene) and hand‐held photometer (iCheck Carotene).ResultsConcentrations of β‐carotene in plasma measured using the POC assay ranged from 0.40 to 15.84 mg/L (n = 166). No differences were observed between methods for assay of plasma (mean ± SD; n = 166): HPLC‐plasma 4.23 ± 2.35 mg/L; POC‐plasma 4.49 ± 2.36 mg/L. Similar good agreement was found when plasma analyzed using HPLC was compared with whole blood analyzed using the POC system (n = 23): HPLC‐plasma 3.46 ± 2.12 mg/L; POC‐whole blood 3.67 ± 2.29 mg/L.ConclusionsConcentrations of β‐carotene can be measured in blood and plasma from cattle easily and rapidly using a POC assay, and results are comparable to those obtained by the highly sophisticated HPLC method. Immediate feedback regarding β‐carotene deficiency facilitates rapid and appropriate optimization of β‐carotene supplementation in feed.
Risk factors for type 2 diabetes: Lessons learned from Japanese Americans in Seattle
Authors: Fujimoto Wilfred Y , Boyko Edward J , Hayashi Tomoshige , Kahn Steven E , Leonetti Donna L , McNeely Marguerite J , Shuman William P 
Published: January 2012

AbstractMigrant Japanese populations in both the USA and Brazil have for a long time shown a higher prevalence of type 2 diabetes than native Japanese, suggesting an interaction of lifestyle and genetic predisposition in the etiology of type 2 diabetes. The overall objective of the Seattle Japanese American Community Diabetes Study was to learn more about the etiology and pathogenesis of type 2 diabetes in Japanese Americans. This metabolically based epidemiological study included extensive assessments of insulin sensitivity, insulin response, and adiposity with the latter including measurements of body fat distribution by both anthropometry and computed tomography. Because of this, the importance of visceral adiposity as a risk factor for abnormal glucose tolerance, hypertension, coronary heart disease and the metabolic syndrome was shown. In conjunction with an examination of diet and physical activity patterns, the result was a clearer understanding of the etiology and pathogenesis of type 2 diabetes in Japanese Americans. We propose that a lifestyle that fosters increased weight gain, especially in the visceral adipose depot, promotes the development of insulin resistance, which in turn exposes an underlying reduced β‐cell reserve in susceptible individuals, resulting in glucose intolerance and, eventually in many, the development of diabetes. We have shown that it might be possible to delay or prevent the development of diabetes through dietary and exercise interventions in individuals identified as having impaired glucose tolerance. The lessons learned from studying migrant Japanese in Seattle might in many ways be applicable to other populations of Asian origin. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00195.x, 2012)
Perceptions of junior doctors in the NHS about their training: results of a regional questionnaire
Authors: Gilbert Alexandra , Hockey Peter , Vaithianathan Rhema , Curzen Nick , Lees Peter 
Published: January 2012

ObjectiveTo explore the views of doctors in training about their current roles and their potential value to the National Health Service (NHS) in improving healthcare quality and productivity.MethodsOnline questionnaire sent via email to 3766 junior doctors (foundation year one to specialist trainee year 3+) in the NHS South Central region.ResultsThe response rate was 1479/3766 (39.3%). Respondents recognised the importance of leadership (89.7%), team working (89.2%) and professionalism (97%). Only 3.4% of junior doctors stated they have never acted in a leadership capacity. However, respondents reported a lack of receptivity from their organisations: the majority responded that they do not feel valued by managers (83.3%), the chief executive (77.7%), the organisation (77.3%), the NHS (79.3%) and consultants (58.2%). 91.2% of respondents have had ideas for improvement in their workplace; however, only 10.7% have had their ideas for change implemented. Respondents who had been on a NHS South Central leadership development course were significantly more likely to feel valued by all groups of staff in their organisation. They were also significantly more likely to report having their ideas implemented.ConclusionsDoctors in training have a desire and perceived ability to contribute to improvement in the NHS but do not perceive their working environment as receptive to their skills. Junior doctors who attend leadership training report higher levels of desire and ability to express these skills. This study suggests junior doctors are an untapped NHS resource and that they and their organisations would benefit from more formalised provision of training in leadership.
Lobar collapse demystified: the chest radiograph with CT correlation
Authors: Mullett Rebecca , Jain Abhishek , Kotugodella Sripali , Curtis John 
Published: January 2012

Abstract
Collapse of a lobe of a lung is an important indicator of a range of conditions, including malignancy. Clinical symptoms and signs may suggest a diagnosis of lobar collapse; however, it is often diagnosed, and always needs to be confirmed, with radiological examination. The radiological signs may be subtle, difficult to interpret and sometimes confusing to both clinicians and radiologists. Although multidetector CT (MDCT) is now widely in use for confirming and diagnosing lobar collapse, the plain chest radiograph is usually the first imaging modality performed and so recognition on the plain film remains of vital importance. The basics of chest radiograph interpretation are reviewed, concentrating on the concepts of radiographic density and the silhouette sign. MDCT images are used to demonstrate the general radiological signs of collapse, and the signs of collapse that are specific to the different lobes of the lung are reviewed.
Chronic kidney disease in snake envenomed patients with acute kidney injury in Sri Lanka: a descriptive study
Authors: Herath H M N J , Wazil A W M , Abeysekara D T D J , Jeewani N D C , Weerakoon K G A D , Ratnatunga N V I , Bandara E H C K , Kularatne S A M 
Published: January 2012

Abstract

Background
Data on the long-term outcomes of acute kidney injury (AKI) in envenomed patients leading to chronic kidney disease (CKD) are scarce. The aim of the study was to investigate this issue and to determine the predictive factors in developing CKD.

Methods
The records of a series of 54 patients who had AKI following a snakebite during the period 2004–2009 and who had been followed up were reviewed in the nephrology unit, Kandy, Sri Lanka. The primary outcome measure was the failure of renal functions to return to normal within 1 year. The renal histology was studied in seven patients.

Results
The mean age of the group was 50 years (SD 13 years) and 39 (72%) patients were men. The offending snakes were Russell's viper and hump-nosed viper in 15 (28%) and 13 (24%) patients, respectively. At 1 year, 20 patients (37%) had developed CKD (CKD group) and the rest (63%) had recovered (recovered group). The acute stage serum creatinine was high in both groups with no difference (on admission, p=0.134; on discharge, p=0.323), but the CKD group showed significantly high serum creatinine at 2 months after AKI (p=0.004). Mean duration of renal replacement therapy (RRT) of the recovered group and CKD group were 7 (SD 5) and 16 (SD 12) days, respectively (p=0.015). Renal histology of six CKD patients showed predominant glomerular sclerosis and interstitial nephritis.

Conclusions
CKD is an outcome of severe AKI following snake envenoming probably predicted by the length of RRT.
Imaging in pulmonary hypertension, part 2: large vessel diseases
Authors: McCann Caroline , Gopalan Deepa , Sheares Karen , Screaton Nicholas 
Published: January 2012

AbstractPulmonary hypertension is defined by physiological parameters but there are numerous causes that differ in their pathogenesis, management and prognosis. Causes include chronic cardiac or pulmonary diseases and diffuse small vessel disease but also a range of large vessel obstructive diseases. The physiological manifestation of all these diseases is increased pulmonary vascular resistance and pulmonary arterial hypertension, and while clinical features may provide a clue to diagnosis, imaging plays a fundamental role in establishing a precise diagnosis and therefore guiding therapy. Chronic thromboembolic pulmonary hypertension (CTEPH) is the most common large vessel cause of pulmonary hypertension. It is increasingly recognised as a major cause of morbidity and mortality which is underdiagnosed and often diagnosed late. The importance of CTEPH is that for patients in whom the distribution of disease lies predominantly in the proximal vasculature there is potential for symptomatic and physiological cure by surgical pulmonary endarterectomy. More distal disease may be suitable for medical management. Increased awareness on behalf of both clinicians and imagers is therefore paramount. However, there are other rare causes or large vessel obstruction/stenosis such as large vessel vasculitis, pulmonary artery tumour, fibrosing mediastinitis, congenital stenosis or extrinsic compression of the pulmonary arteries/veins. Atypical imaging appearance such as unilateral central pulmonary artery obstruction should lead to consideration of a diagnosis other than CTEPH.
Tumor-Derived Chemokine CCL5 Enhances TGF-β–Mediated Killing of CD8+ T Cells in Colon Cancer by T-Regulatory Cells
Authors: Chang Li-Yuan , Lin Yung-Chang , Mahalingam Jayashri , Huang Ching-Tai , Chen Ten-Wen , Kang Chiao-Wen , Peng Hui-Min , Chu Yu-Yi , Chiang Jy-Ming , Dutta Avijit , Day Yuan-Ji , Chen Tse-Ching , Yeh Chau-Ting , Lin Chun-Yen 
Published: January 2012

Abstract
Chemokine CCL5/RANTES is highly expressed in cancer where it contributes to inflammation and malignant progression. In this study, we show that CCL5 plays a critical role in immune escape in colorectal cancer. We found that higher levels of CCL5 expression in human and murine colon tumor cells correlated with higher levels of apoptosis of CD8+ T cells and infiltration of T-regulatory cells (Treg). In mouse cells, RNA interference (RNAi)-mediated knockdown of CCL5 delayed tumor growth in immunocompetent syngeneic hosts but had no effect on tumor growth in immunodeficient hosts. Reduced tumor growth was correlated with a reduction in Treg infiltration and CD8+ T-cell apoptosis in tumors. Notably, we found that CCL5 enhanced the cytotoxicity of Treg against CD8+ T cells. We also found tumor growth to be diminished in mice lacking CCR5, a CCL5 receptor, where a similar decrease in both Treg cell infiltration and CD8+ T-cell apoptosis was noted. TGF-β signaling blockade diminished apoptosis of CD8+ T cells, implicating TGF-β as an effector of CCL5 action. In support of this concept, CCL5 failed to enhance the production of TGF-β by CCR5-deficient Treg or to enhance their cytotoxic effects against CD8+ T cells. CCR5 signaling blockade also diminished the in vivo suppressive capacity of Treg in inhibiting the antitumor responses of CD8+ T cells, in the same way as CCL5 signaling blockade. Together, our findings establish that CCL5/CCR5 signaling recruits Treg to tumors and enhances their ability to kill antitumor CD8+ T cells, thereby defining a novel mechanism of immune escape in colorectal cancer. Cancer Res; 72(5); 1092–102. ©2012 AACR.
Extracellular Matrix Protein CCN1 Limits Oncolytic Efficacy in Glioma
Authors: Haseley Amy , Boone Sean , Wojton Jeffrey , Yu Lianbo , Yoo Ji Young , Yu Jianhua , Kurozumi Kazuhiko , Glorioso Joseph C. , Caligiuri Michael A. , Kaur Balveen 
Published: January 2012

Abstract
Oncolytic viral therapy has been explored widely as an option for glioma treatment but its effectiveness has remained limited. Cysteine rich 61 (CCN1) is an extracellular matrix (ECM) protein elevated in cancer cells that modulates their adhesion and migration by binding cell surface receptors. In this study, we examined a hypothesized role for CCN1 in limiting the efficacy of oncolytic viral therapy for glioma, based on evidence of CCN1 induction that occurs in this setting. Strikingly, we found that exogenous CCN1 in glioma ECM orchestrated a cellular antiviral response that reduced viral replication and limited cytolytic efficacy. Gene expression profiling and real-time PCR analysis revealed a significant induction of type-I interferon responsive genes in response to CCN1 exposure. This induction was accompanied by activation of the Jak/Stat signaling pathway, consistent with induction of an innate antiviral cellular response. Both effects were mediated by the binding of CCN1 to the cell surface integrin α6β1, activating its signaling and leading to rapid secretion of interferon-α, which was essential for the innate antiviral effect. Together, our findings reveal how an integrin signaling pathway mediates activation of a type-I antiviral interferon response that can limit the efficacy of oncolytic viral therapy. Furthermore, they suggest therapeutic interventions to inhibit CCN1–integrin α6 interactions to sensitize gliomas to viral oncolysis. Cancer Res; 72(6); 1353–62. ©2012 AACR.
Leptin Mediates Tumor–Stromal Interactions That Promote the Invasive Growth of Breast Cancer Cells
Authors: Barone Ines , Catalano Stefania , Gelsomino Luca , Marsico Stefania , Giordano Cinzia , Panza Salvatore , Bonofiglio Daniela , Bossi Gianluca , Covington Kyle R. , Fuqua Suzanne A.W. , Andò Sebastiano 
Published: January 2012

AbstractObesity confers risks to cancer development and progression but the mechanisms underlying these risks remain unclear. In this study, we identify a role for the obesity cytokine leptin, which has been implicated previously in breast cancer development, as a determinant for the tumor-promoting activity of cancer-associated fibroblasts (CAF) in both wild-type (WT) and K303R mutant estrogen receptor-α (ERα)–expressing breast cancer cells. Human CAFs stimulated a greater increase in the proliferation and migration of breast cancer cells expressing the K303R-ERα hyperactive receptor than WT-ERα–expressing cells. A concomitant increase was seen in leptin receptor isoform expression and activation of the leptin signaling pathway in cells expressing K303R-ERα compared with WT-ERα, correlating with leptin effects on cell growth, motility, and invasiveness in mutant cells. Epidermal growth factor and other factors secreted by K303R-ERα cells stimulated CAF proliferation, migration, and subsequent leptin secretion. Moreover, K303R-ERα expression generated a leptin hypersensitive phenotype in vivo. Together, our results reveal a bidirectional cross-talk between breast cancer cells and “educated” CAFs that drives tumor progression via leptin signaling. In elucidating a mechanism that connects obesity and cancer, these findings reinforce the concept that blocking cancer–stromal cell communication may represent an effective strategy for targeted therapy of breast cancer. Cancer Res; 72(6); 1416–27. ©2012 AACR.
Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression
Authors: Roth Felix , De La Fuente Adriana C. , Vella Jennifer L. , Zoso Alessia , Inverardi Luca , Serafini Paolo 
Published: January 2012

AbstractIn addition to promoting tumor progression and metastasis by enhancing angiogenesis and invasion, myeloid-derived suppressor cells (MDSC) and tumor-associated macrophage (TAM) also inhibit antitumor T-cell functions and limit the efficacy of immunotherapeutic interventions. Despite the importance of these leukocyte populations, a simple method for their specific depletion has not been developed. In this study, we generated an RNA aptamer that blocks the murine or human IL-4 receptor-α (IL4Rα or CD124) that is critical for MDSC suppression function. In tumor-bearing mice, this anti–IL4Rα aptamer preferentially targeted MDSCs and TAM and unexpectedly promoted their elimination, an effect that was associated with an increased number of tumor-infiltrating T cells and a reduction in tumor growth. Mechanistic investigations of aptamer-triggered apoptosis in MDSCs confirmed the importance of IL4Ra–STAT6 pathway activation in MDSC survival. Our findings define a straightforward strategy to deplete MDSCs and TAMs in vivo, and they strengthen the concept that IL4Rα signaling is pivotal for MDSC survival. More broadly, these findings suggest therapeutic strategies based on IL4Rα signaling blockades to arrest an important cellular mechanism of tumoral immune escape mediated by MDSCs and TAM in cancer. Cancer Res; 72(6); 1373–83. ©2012 AACR.
3′-UTR and Functional Secretor Haplotypes in Mannose-Binding Lectin 2 Are Associated with Increased Colon Cancer Risk in African Americans
Authors: Zanetti Krista A. , Haznadar Majda , Welsh Judith A. , Robles Ana I. , Ryan Bríd M. , McClary Andrew C. , Bowman Elise D. , Goodman Julie E. , Bernig Toralf , Chanock Stephen J. , Harris Curtis C. 
Published: January 2012

AbstractBecause chronic intestinal inflammation is a risk factor for colorectal cancer, we hypothesized that genetic variants of inflammatory mediators, such as mannose-binding lectin 2 (MBL2), are associated with colon cancer susceptibility. Here, we report the association of 24 MBL2 single-nucleotide polymorphisms (SNP) and corresponding haplotypes with colon cancer risk in a case–control study. Four SNPs in the 3′-untranslated region (UTR) of the gene (rs10082466, rs2120132, rs2099902, and rs10450310) were associated with an increased risk of colon cancer in African Americans. ORs for homozygous variants versus wild-type ranged from 3.17 [95% confidence interval (CI), 1.57–6.40] to 4.51 (95% CI, 1.94–10.50), whereas the 3′-UTR region haplotype consisting of these four variants had an OR of 2.10 (95% CI, 1.42–3.12). The C allele of rs10082466 exhibited a binding affinity of miR-27a and this allele was associated with both lower MBL plasma levels and activity. We found that 5′ secretor haplotypes known to correlate with moderate and low MBL serum levels exhibited associations with increased risk of colon cancer in African Americans, specifically as driven by two haplotypes, LYPA and LYQC, relative to the referent HYPA haplotype (LYPA: OR, 2.60; 95% CI, 1.33–5.08 and LYQC: OR, 2.28; 95% CI, 1.20–4.30). Similar associations were not observed in Caucasians. Together, our results support the hypothesis that genetic variations in MBL2 increase colon cancer susceptibility in African Americans. Cancer Res; 72(6); 1467–77. ©2012 AACR.