bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnosis, prognosis and classification of early arthritis: results of a systematic review informing the 2016 update of the EULAR recommendations for the management of early arthritis
Authors: Hua Charlotte , Daien Claire I , Combe Bernard , Landewe Robert 
Published: January 2017

ObjectiveTo update the evidence pertaining to the diagnosis, prognosis and classification of patients with early arthritis (EA), and to inform the 2016 European League Against Rheumatism (EULAR) recommendations for the management of patients with EA.MethodsMEDLINE, EMBASE and Cochrane databases were searched up to October 2015. The first part of the systematic literature review (SLR) involved a search for studies investigating the recognition and referral of EA. The second part involved a search for studies to identify the place of laboratory and imaging tests in establishing a diagnosis and a prognosis in patients with EA.ResultsRegarding the issue of referral of patients with EA (1643 hits), 4 studies were included. These studies were in support of early referral for patients with EA. Regarding the issue of diagnosis and prognosis of patients with EA (11 435 hits), 88 studies were included, evaluating mainly the value of rheumatoid factor (RF) and anticitrullinated-peptide antibodies (ACPAs). Sensitivity of these antibodies for a RA diagnosis in patients with EA was moderate (40–80%). Specificity was higher, notably for ACPAs (frequently >80%). ACPAs also showed better prognostic performance than RF (negative predictive values around 80%). We confirmed that structural damage on baseline X-rays is predictive of further radiographic progression in patients with EA. Regarding other imaging modalities, data are sparse.ConclusionsThis SLR highlights the importance of early referral for patients with EA and confirms that RF and mainly ACPAs as well as a search for structural X-rays changes may help in the diagnosis and prognosis of patients with EA.
A novel complex I inhibitor protects against hypertension-induced left ventricular hypertrophy
Authors: Matsumura Nobutoshi , Robertson Ian M. , Hamza Shereen M. , Soltys Carrie-Lynn M. , Sung Miranda M. , Masson Grant , Beker Donna L. , Dyck Jason R. B. 
Published: January 2017

Since left ventricular hypertrophy (LVH) increases the susceptibility for the development of other cardiac conditions, pharmacotherapy that mitigates pathological cardiac remodeling may prove to be beneficial in patients with LVH. Previous work has shown that the activation of the energy-sensing kinase AMP-activated protein kinase (AMPK) can inhibit some of the molecular mechanisms that are involved in LVH. Of interest, metformin activates AMPK through its inhibition of mitochondrial complex I in the electron transport chain and can prevent LVH induced by pressure overload. However, metformin has additional cellular effects unrelated to AMPK activation, raising questions about whether mitochondrial complex I inhibition is sufficient to reduce LVH. Herein, we characterize the cardiac effects of a novel compound (R118), which is a more potent complex I inhibitor than metformin and is thus used at a much lower concentration. We show that R118 activates AMPK in the cardiomyocyte, inhibits multiple signaling pathways involved in LVH, and prevents Gq protein-coupled receptor agonist-induced prohypertrophic signaling. We also show that in vivo administration of R118 prevents LVH in a mouse model of hypertension, suggesting that R118 can directly modulate the response of the cardiomyocyte to stress. Of importance, we also show that while R118 treatment prevents adaptive remodelling in response to elevated afterload, it does so without compromising systolic function, improves myocardial energetics, and prevents a decline in diastolic function in hypertensive mice. Taken together, our data suggest that inhibition of mitochondrial complex I may be worthy of future investigation for the treatment of LVH. NEW & NOTEWORTHY Inhibition of mitochondrial complex I by R118 reduces left ventricular hypertrophy (LVH) and improves myocardial energetics as well as diastolic function without compromising systolic function. Together, these effects demonstrate the therapeutic potential of complex I inhibitors in the treatment of LVH, even in the presence of persistent hypertension.
Blood flow patterns underlie developmental heart defects
Authors: Midgett Madeline , Thornburg Kent , Rugonyi Sandra 
Published: January 2017

Although cardiac malformations at birth are typically associated with genetic anomalies, blood flow dynamics also play a crucial role in heart formation. However, the relationship between blood flow patterns in the early embryo and later cardiovascular malformation has not been determined. We used the chicken embryo model to quantify the extent to which anomalous blood flow patterns predict cardiac defects that resemble those in humans and found that restricting either the inflow to the heart or the outflow led to reproducible abnormalities with a dose-response type relationship between blood flow stimuli and the expression of cardiac phenotypes. Constricting the outflow tract by 10–35% led predominantly to ventricular septal defects, whereas constricting by 35–60% most often led to double outlet right ventricle. Ligation of the vitelline vein caused mostly pharyngeal arch artery malformations. We show that both cardiac inflow reduction and graded outflow constriction strongly influence the development of specific and persistent abnormal cardiac structure and function. Moreover, the hemodynamic-associated cardiac defects recapitulate those caused by genetic disorders. Thus our data demonstrate the importance of investigating embryonic blood flow conditions to understand the root causes of congenital heart disease as a prerequisite to future prevention and treatment. NEW & NOTEWORTHY Congenital heart defects result from genetic anomalies, teratogen exposure, and altered blood flow during embryonic development. We show here a novel “dose-response” type relationship between the level of blood flow alteration and manifestation of specific cardiac phenotypes. We speculate that abnormal blood flow may frequently underlie congenital heart defects.
Susceptibility to high-altitude pulmonary edema is associated with a more uniform distribution of regional specific ventilation
Authors: Patz Michael D. , Sá Rui C. , Darquenne Chantal , Elliott Ann R. , Asadi Amran K. , Theilmann Rebecca J. , Dubowitz David J. , Swenson Erik R. , Prisk G. Kim , Hopkins Susan R. 
Published: January 2017

High-altitude pulmonary edema (HAPE) is a potentially fatal condition affecting high-altitude sojourners. The biggest predictor of HAPE development is a history of prior HAPE. Magnetic resonance imaging (MRI) shows that HAPE-susceptible (with a history of HAPE), but not HAPE-resistant (with a history of repeated ascents without illness) individuals develop greater heterogeneity of regional pulmonary perfusion breathing hypoxic gas (O2= 12.5%), consistent with uneven hypoxic pulmonary vasoconstriction (HPV). Why HPV is uneven in HAPE-susceptible individuals is unknown but may arise from regionally heterogeneous ventilation resulting in an uneven stimulus to HPV. We tested the hypothesis that ventilation is more heterogeneous in HAPE-susceptible subjects ( n = 6) compared with HAPE-resistant controls ( n = 7). MRI specific ventilation imaging (SVI) was used to measure regional specific ventilation and the relative dispersion (SD/mean) of SVI used to quantify baseline heterogeneity. Ventilation heterogeneity from conductive and respiratory airways was measured in normoxia and hypoxia (O2= 12.5%) using multiple-breath washout and heterogeneity quantified from the indexes Scondand Sacin, respectively. Contrary to our hypothesis, HAPE-susceptible subjects had significantly lower relative dispersion of specific ventilation than the HAPE-resistant controls [susceptible = 1.33 ± 0.67 (SD), resistant = 2.36 ± 0.98, P = 0.05], and Sacintended to be more uniform (susceptible = 0.085 ± 0.009, resistant = 0.113 ± 0.030, P = 0.07). Scondwas not significantly different between groups (susceptible = 0.019 ± 0.007, resistant = 0.020 ± 0.004, P = 0.67). Sacinand Sconddid not change significantly in hypoxia ( P = 0.56 and 0.19, respectively). In conclusion, ventilation heterogeneity does not change with short-term hypoxia irrespective of HAPE susceptibility, and lesser rather than greater ventilation heterogeneity is observed in HAPE-susceptible subjects. This suggests that the basis for uneven HPV in HAPE involves vascular phenomena.NEW & NOTEWORTHY Uneven hypoxic pulmonary vasoconstriction (HPV) is thought to incite high-altitude pulmonary edema (HAPE). We evaluated whether greater heterogeneity of ventilation is also a feature of HAPE-susceptible subjects compared with HAPE-resistant subjects. Contrary to our hypothesis, ventilation heterogeneity was less in HAPE-susceptible subjects and unaffected by hypoxia, suggesting a vascular basis for uneven HPV.
Contractile efficiency of dystrophic mdx mouse muscle: in vivo and ex vivo assessment of adaptation to exercise of functional end points
Authors: Capogrosso Roberta Francesca , Mantuano Paola , Cozzoli Anna , Sanarica Francesca , Massari Ada Maria , Conte Elena , Fonzino Adriano , Giustino Arcangela , Rolland Jean-Francois , Quaranta Angelo , De Bellis Michela , Camerino Giulia Maria , Grange Robert W. , De Luca Annamaria 
Published: January 2017

Progressive weakness is a typical feature of Duchenne muscular dystrophy (DMD) patients and is exacerbated in the benign mdx mouse model by in vivo treadmill exercise. We hypothesized a different threshold for functional adaptation of mdx muscles in response to the duration of the exercise protocol. In vivo weakness was confirmed by grip strength after 4, 8, and 12 wk of exercise in mdx mice. Torque measurements revealed that exercise-related weakness in mdx mice correlated with the duration of the protocol, while wild-type (WT) mice were stronger. Twitch and tetanic forces of isolated diaphragm and extensor digitorum longus (EDL) muscles were lower in mdx compared with WT mice. In mdx, both muscle types exhibited greater weakness after a single exercise bout, but only in EDL after a long exercise protocol. As opposite to WT muscles, mdx EDL ones did not show any exercise-induced adaptations against eccentric contraction force drop. qRT-PCR analysis confirmed the maladaptation of genes involved in metabolic and structural remodeling, while damage-related genes remained significantly upregulated and angiogenesis impaired. Phosphorylated AMP kinase level increased only in exercised WT muscle. The severe histopathology and the high levels of muscular TGF-β1 and of plasma matrix metalloproteinase-9 confirmed the persistence of muscle damage in mdx mice. Therefore, dystrophic muscles showed a partial degree of functional adaptation to chronic exercise, although not sufficient to overcome weakness nor signs of damage. The improved understanding of the complex mechanisms underlying maladaptation of dystrophic muscle paves the way to a better managment of DMD patients.NEW & NOTEWORTHY We focused on the adaptation/maladaptation of dystrophic mdx mouse muscles to a standard protocol of exercise to provide guidance in the development of more effective drug and physical therapies in Duchenne muscular dystrophy. The mdx muscles showed a modest functional adaptation to chronic exercise, but it was not sufficient to overcome the progressive in vivo weakness, nor to counter signs of muscle damage. Therefore, a complex involvement of multiple systems underlies the maladaptive response of dystrophic muscle.
Pathology-Driven Comprehensive Proteomic Profiling of the Prostate Cancer Tumor Microenvironment
Authors: Staunton Lisa , Tonry Claire , Lis Rosina , Espina Virginia , Liotta Lance , Inzitari Rosanna , Bowden Michaela , Fabre Aurelie , O'Leary John , Finn Stephen P. , Loda Massimo , Pennington Stephen R. 
Published: January 2017

Abstract
Prostate cancer is the second most common cancer in men worldwide. Gleason grading is an important predictor of prostate cancer outcomes and is influential in determining patient treatment options. Clinical decisions based on a Gleason score of 7 are difficult as the prognosis for individuals diagnosed with Gleason 4+3 cancer is much worse than for those diagnosed with Gleason 3+4 cancer. Laser capture microdissection (LCM) is a highly precise method to isolate specific cell populations or discrete microregions from tissues. This report undertook a detailed molecular characterization of the tumor microenvironment in prostate cancer to define the proteome in the epithelial and stromal regions from tumor foci of Gleason grades 3 and 4. Tissue regions of interest were isolated from several Gleason 3+3 and Gleason 4+4 tumors using telepathology to leverage specialized pathology expertise to support LCM. Over 2,000 proteins were identified following liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of all regions of interest. Statistical analysis revealed significant differences in protein expression (&gt;100 proteins) between Gleason 3 and Gleason 4 regions—in both stromal and epithelial compartments. A subset of these proteins has had prior strong association with prostate cancer, thereby providing evidence for the authenticity of the approach. Finally, validation of these proteins by immunohistochemistry has been obtained using an independent cohort of prostate cancer tumor specimens.
Implications: This unbiased strategy provides a strong foundation for the development of biomarker protein panels with significant diagnostic and prognostic potential. Mol Cancer Res; 15(3); 281–93. ©2017 AACR.
Targeting HDAC3 in CREBBP-Mutant Lymphomas Counterstrikes Unopposed Enhancer Deacetylation of B-cell Signaling and Immune Response Genes
Authors: Höpken Uta E. 
Published: January 2017

Abstract
Summary: The cellular phenotype of B-cell lymphomas arising from B cells undergoing germinal center reactions, such as follicular lymphoma and diffuse large B-cell lymphoma, is strongly shaped by mutations in chromatin-modifying genes. The work presented by Jiang and colleagues addresses how somatic mutations in CREBBP disable acetylation and cause unopposed deacetylation by BCL6/SMRT/HDAC3 complexes on enhancers of B-cell signaling and immune response genes. This opens a therapeutic avenue toward targeted inhibition of CREBBP-mutant lymphomas by HDAC inhibitors. Cancer Discov; 7(1); 14–6. ©2017 AACR.
See related article by Jiang et al., p. 38.
Repurposing Antiestrogens for Tumor Immunotherapy
Authors: Welte Thomas , Zhang Xiang H.-F. , Rosen Jeffrey M. 
Published: January 2017

Abstract
Summary: Svoronos and colleagues observed estrogen receptor alpha–positive cells in the tumor stroma of patients with ovarian cancer that appeared to be independent of both the tumor's estrogen receptor status and tumor type. These cells were identified as immunosuppressive myeloid-derived suppressor cells (MDSC) and could be targeted by antiestrogen therapy, thereby leading to the hypothesis that endocrine therapy when combined with immunotherapy may provide a potential therapeutic benefit by helping to reduce immunosuppressive MDSCs. Cancer Discov; 7(1); 17–9. ©2017 AACR.
See related article by Svoronos et al., 72.
Turismo de Base Comunitária: outras economias na mira da emancipação social
Authors: Leão Carolina Valéria De Moura 
Published: January 2017

O sentido de comunidade tem sido a ideia-chave do Turismo de Base Comunitária (TBC), associando formas comuns de organização e gestão, em que esta é a principal beneficiária. Este artigo procura conhecer que mecanismos colaborativos e de gestão as comunidades recetoras têm desenvolvido, que sinalizem outras lógicas assentes na autogestão e na solidariedade, contrariamente à tendência da concentração empresarial e do lucro. Por sua vez, se estes se refletem em uma proposta de transformação social, com o aparecimento de novos sujeitos protagonistas no processo. Os elementos empíricos são obtidos a partir do recorte das informações incluídas no relatório de avaliação final externa de um projeto de TBC, em Timor Leste, tendo como foco três comunidades/cooperativas. O estudo revela a existência de novos sujeitos que se organizam na partilha de poderes e saberes, a partir de códigos de conduta e um conjunto de procedimentos de gestão colaborativa, apontando para um horizonte de emancipação social.
ENTRE A ESSÊNCIA E A EXISTÊNCIA: A CORRESPONDÊNCIA DE ESPINOSA A HUDDE
Authors: Rodrigues Juarez Lopes 
Published: January 2017

O objetivo deste artigo é analisar o conteúdo das Cartas 34, 35 e 36 da Correspondência de Espinosa a Hudde. Nele podemos perceber o esforço e engenhosidade do filósofo em conduzir o seu interlocutor a assentir à primeira definição da Ética, a definição de causa sui. Hudde, matemático de formação, se esforça em compreender como o filósofo pode demonstrar que a unicidade de Deus possa ser deduzida exclusivamente do fato de que sua natureza ou essência envolve existência necessária. É através do estatuto causal da definição verdadeira que Espinosa poderá conduzi-lo, e evitar, assim, que caia nos paradoxos do uno e do múltiplo, da distinção real e da numérica. Dada a incapacidade do matemático em assentir à definição genética de Deus, o filósofo o conduzirá a assentir indiretamente à definição através do procedimento de demonstração negativa ou por redução ao absurdo. Esse movimento intelectual explicitará os propria de Deus: a eternidade, a simplicidade, a infinitude, a indivisibilidade, a perfeição e a unicidade.
Um Estranho em Goa: viagem transitiva a um Oriente em demanda
Authors: Mata Inocência 
Published: January 2017

A obra de José Eduardo Agualusa (Huambo, Angola, 1960) tem a particularidade de não se deter nem numa prática genológica (a sua bibliografia inclui romances, contos, crónicas, apontamentos narrativos e alguma poesia) nem numa área temática ou uma geografia – espacial, temporal ou cultural. Com efeito, as suas personagens são normalmente marcadas por descontinuidades geográficas e históricas, com trajectórias que se cruzam numa “perspectiva de contacto” que potencia conexões e interacções de vária ordem entre sujeitos diferentes, em espácio-temporalidades diversificadas. Tais arborescências ficcionais, sobretudo romanescas, embora nem sempre suficientemente amplificadoras para criar sentidos cosmopolitas, são construtoras de sujeitos transitivos e geradoras de significados transculturativos. É o que acontece em Um Estranho em Goa, romance que, oscilando entre narrativa de viagens e construção ficcional do real, apresenta diferentes modalidades da reinvenção da identidade goesa, trazendo à cena literária trânsitos e conexões orientais num processo de resgate das margens das representações político-ideológicas do outro, apresentado na sua outridade – portanto, como possibilidade do diverso.
Representações da Goa católica pós-colonial e a "poética da sujidade" na crónica de viagem “Goa the Unique” (1964), de Graham Greene
Authors: Puga Rogerio Miguel 
Published: January 2017

Em Dezembro de 1963, o conhecido romancista Graham Greene (1904-1991) visita Goa em trabalho para o jornal Sunday Times, no qual vem a publicar, no ano seguinte, uma crónica intitulada “Goa the Unique”. O presente artigo analisa a representação da Goa católica dois anos após o final da administração colonial portuguesa (quando o futuro político do território era ainda uma incógnita) através dos topoi da singularidade da Goa católica e higiénica face a uma Índia ameaçadora, suja e doente (poética da sujidade), metáforas que eram, há muito tempo, recorrentes na literatura inglesa.
Olfactomedin 2 Regulates Smooth Muscle Phenotypic Modulation and Vascular Remodeling Through Mediating Runt-Related Transcription Factor 2 Binding to Serum Response Factor
Authors: Shi Ning , Li Chen-Xiao , Cui Xiao-Bing , Tomarev Stanislav I. , Chen Shi-You 
Published: January 2017

Objective—
The objective of this study is to investigate the role and underlying mechanism of Olfactomedin 2 (Olfm2) in smooth muscle cell (SMC) phenotypic modulation and vascular remodeling.

Approach and Results—
Platelet-derived growth factor-BB induces Olfm2 expression in primary SMCs while modulating SMC phenotype as shown by the downregulation of SMC marker proteins. Knockdown of Olfm2 blocks platelet-derived growth factor-BB–induced SMC phenotypic modulation, proliferation, and migration. Conversely, Olfm2 overexpression inhibits SMC marker expression. Mechanistically, Olfm2 promotes the interaction of serum response factor with the runt-related transcription factor 2 that is induced by platelet-derived growth factor-BB, leading to a decreased interaction between serum response factor and myocardin, causing a repression of SMC marker gene transcription and consequently SMC phenotypic modulation. Animal studies show that Olfm2 is upregulated in balloon-injured rat carotid arteries. Knockdown of Olfm2 effectively inhibits balloon injury–induced neointima formation. Importantly, knockout of Olfm2 in mice profoundly suppresses wire injury–induced neointimal hyperplasia while restoring SMC contractile protein expression, suggesting that Olfm2 plays a critical role in SMC phenotypic modulation in vivo.

Conclusions—
Olfm2 is a novel factor mediating SMC phenotypic modulation. Thus, Olfm2 may be a potential target for treating injury-induced proliferative vascular diseases.
Cellular Repressor of E1A-Stimulated Genes Is a Critical Determinant of Vascular Remodeling in Response to Angiotensin II
Authors: Li Yang , Liu Yanxia , Tian Xiaoxiang , Zhang Yan , Song Haixu , Liu Meili , Zhang Xiaolin , Liu Haiwei , Zhang Jian , Zhang Quanyu , Liu Dan , Peng Chengfei , Yan Chenghui , Han Yaling 
Published: January 2017

Objective—
Cellular repressor of E1A-stimulated genes (CREG) is a lysosomal glycoprotein implicated in maintaining vascular homeostasis. Here, we have hypothesized that CREG is a critical target of intervention for the prevention of hypertensive vascular remodeling.

Approach and Results—

CREG gene expression was significantly decreased accompanied by an upregulated expression of angiotensin II (Ang II) in remodeled vascular tissues of high salt–induced Dahl salt-sensitive rats and Ang II–induced mice. In particular, the downregulation of CREG gene was Ang II specific and independent from blood pressure. Prominent medial hypertrophy and vascular fibrosis in both thoracic aortas and mesenteric arteries were observed in CREG
+/−
mice infused with Ang II than in CREG
+/+
mice, but blunted response in CREG
+/+
mice received recombinant human CREG protein, suggesting that changes in CREG expression account for the different phenotype between genotypes. Within a tiled promoter array, E26 transformation-specific-1 binds to CREG promoter at high stringency with the stimulation of Ang II. Moreover, the Ang II–induced E26 transformation-specific-1 directly interacted with the CREG promoter (-1179 and -271 bp) and inhibited its transcription in vascular smooth muscle cells. Selective, pharmacological inhibition of E26 transformation-specific-1 led to restoration of CREG expression in aortas and rescue of experimental vascular remodeling by systemic administration of dominant negative E26 transformation-specific-1 membrane-permeable peptides.

Conclusions—
CREG is a novel mediator of vascular remodeling in response to Ang II and may be an attractive therapeutic target for prevention of vascular diseases.