bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of biological and targeted-synthetic DMARDs: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis
Authors: Sepriano Alexandre , Regel Andrea , van der Heijde Désirée , Braun Jürgen , Baraliakos Xenofon , Landewé Robert , Van den Bosch Filip , Falzon Louise , Ramiro Sofia 
Published: January 2017

ObjectivesTo update the evidence for the efficacy and safety of (b)biological and (ts)targeted-synthetic disease-modifying anti-rheumatic drugs (DMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2016 update of the Assessment of SpondyloArthritis international Society/European League Against Rheumatism (ASAS/EULAR) recommendations for the management of axSpA.MethodsSystematic literature review (2009–2016) for randomised controlled trials (RCT), including long-term extensions, strategy trials and observational studies (the latter was only for safety assessment and a comparator was required). Interventions were any bDMARD or tsDMARD. All relevant efficacy and safety outcomes were included.Results76 papers and 24 abstracts fulfilled the inclusion criteria. Large treatment effects were found both in radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA) for all tumour necrosis factor inhibitors (TNFi) (NNT to achieve ASAS40 response ranged between 2.6–5.2 for r-axSpA and 2.3–5.4 for nr-axSpA). For nr-axSpA, efficacy was superior for those who had objective signs of inflammation (positive C reactive protein or inflammation on MRI-SI). Secukinumab 150 mg has shown efficacy in two phase 3 RCTs (NNT to achieve ASAS40 response: 3.4 and 4.0). Ustekinumab and tofacitinib have shown positive results in phase 2/proof-of-concept trials; trials with apremilast, rituximab, interleukin (IL)-6 antagonists and abatacept have failed their primary end points. New (unknown) safety signals were not found in the trials but long-term observational safety data for TNFi are still scarce.ConclusionsNew evidence supports the efficacy and safety of TNFi both in r-axSpA and nr-axSpA. Secukinumab is the first drug targeting the IL-17 pathway in r-axSpA that has shown efficacy.
Determinants of the impact of blood pressure variability on neurological outcome after acute ischaemic stroke
Authors: de Havenon Adam , Bennett Alicia , Stoddard Gregory J , Smith Gordon , Chung Lee , O'Donnell Steve , McNally J Scott , Tirschwell David , Majersik Jennifer J 
Published: January 2017

IntroductionIncreased blood pressure variability (BPV) is detrimental after acute ischaemic stroke, but the interaction between BPV and neuroimaging factors that directly influence stroke outcome has not been explored.MethodsWe retrospectively reviewed inpatients from 2007 to 2014 with acute anterior circulation ischaemic stroke, CT perfusion and angiography at hospital admission, and a modified Rankin Scale (mRS) 30–365 days after stroke onset. BPV indices included SD, coefficient of variation and successive variation of the systolic blood pressure between 0 and 120 hours after admission. Ordinal logistic regression models were fitted to mRS with predictor variables of BPV indices. Models were further stratified by CT perfusion volumetric measurements, proximal vessel occlusion and collateral score.Results110 patients met the inclusion criteria. The likelihood of a 1-point rise in the mRS increased with every 10 mm Hg increase in BPV (OR for the 3 BPV indices ranged from 2.27 to 5.54), which was more pronounced in patients with larger ischaemic core volumes (OR 8.37 to 18.0) and larger hypoperfused volumes (OR 6.02 to 15.4). This association also held true for patients with larger mismatch volume, proximal vessel occlusion and good collateral vessels.ConclusionsThese results indicate that increased BPV is associated with worse neurological outcome after stroke, particularly in patients with a large lesion core volume, concurrent viable ischaemic penumbra, proximal vessel occlusion and good collaterals. This subset of patients, who are often not candidates for or fail acute stroke therapies such as intravenous tissue plasminogen activator or endovascular thrombectomy, may benefit from interventions aimed at reducing BPV.
Peroxisome proliferator-activated receptor-α expression induces alterations in cardiac myofilaments in a pressure-overload model of hypertrophy
Authors: Karam Chehade N. , Warren Chad M. , Henze Marcus , Banke Natasha H. , Lewandowski E. Douglas , Solaro R. John 
Published: January 2017

Although alterations in fatty acid (FA) metabolism have been shown to have a negative impact on contractility of the hypertrophied heart, the targets of action remain elusive. In this study we compared the function of skinned fiber bundles from transgenic (Tg) mice that overexpress a relatively low level of the peroxisome proliferator-activated receptor α (PPARα), and nontransgenic (NTg) littermates. The mice (NTg-T and Tg-T) were stressed by transverse aortic constriction (TAC) and compared with shams (NTg-S and Tg-S). There was an approximate 4-fold increase in PPARα expression in Tg-S compared with NTg-S, but Tg-T hearts showed the same PPARα expression as NTg-T. Expression of PPARα did not alter the hypertrophic response to TAC but did reduce ejection fraction (EF) in Tg-T hearts compared with other groups. The rate of actomyosin ATP hydrolysis was significantly higher in Tg-S skinned fiber bundles compared with all other groups. Tg-T hearts showed an increase in phosphorylation of specific sites on cardiac myosin binding protein-C (cMyBP-C) and β-myosin heavy chain isoform. These results advance our understanding of potential signaling to the myofilaments induced by altered FA metabolism under normal and pathological states. We demonstrate that chronic and transient PPARα activation during pathological stress alters myofilament response to Ca2+through a mechanism that is possibly mediated by MyBP-C phosphorylation and myosin heavy chain isoforms.NEW & NOTEWORTHY Data presented here demonstrate novel signaling to sarcomeric proteins by chronic alterations in fatty acid metabolism induced by PPARα. The mechanism involves modifications of key myofilament regulatory proteins modifying cross-bridge dynamics with differential effects in controls and hearts stressed by pressure overload.
Exosomes from pediatric dilated cardiomyopathy patients modulate a pathological response in cardiomyocytes
Authors: Jiang Xuan , Sucharov Juliana , Stauffer Brian L. , Miyamoto Shelley D. , Sucharov Carmen C. 
Published: January 2017

Stimulation of the renin-angiotensin-aldosterone system (RAAS) and β-adrenergic receptors plays an important role in adult heart failure (HF). Despite the demonstrated benefits of RAAS inhibition and β-adrenergic receptor blockade in adult HF patients, no substantial improvement in survival rate has been observed in children with HF. This suggests that the underlying disease mechanism is uniquely regulated in pediatric HF. Here, we show that treatment of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) with serum from pediatric dilated cardiomyopathy (DCM) patients induces pathological changes in gene expression, which occur independently of the RAAS and adrenergic systems, suggesting that serum circulating factors play an important role in cardiac remodeling. Furthermore, exosomes purified from DCM serum induced pathological changes in gene expression in NRVMs and iPSC-CMs. Our results suggest that DCM serum exosomes mediate pathological responses in cardiomyocytes and may propagate the pediatric HF disease process, representing a potential novel therapeutic target specific to this population.NEW & NOTEWORTHY The results of this work could alter the present paradigm of basing clinical pediatric heart failure (HF) treatment on outcomes of adult HF clinical trials. The use of serum-treated primary cardiomyocytes may define age-specific mechanisms in pediatric HF with the potential to identify unique age-appropriate and disease-specific therapy.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/exosomes-in-pediatric-dilated-cardiomyopathy/ .
Effective Combination Therapies for B-cell Lymphoma Predicted by a Virtual Disease Model
Authors: Du Wei , Goldstein Rebecca , Jiang Yanwen , Aly Omar , Cerchietti Leandro , Melnick Ari , Elemento Olivier 
Published: January 2017

Abstract
The complexity of cancer signaling networks limits the efficacy of most single-agent treatments and brings about challenges in identifying effective combinatorial therapies. In this study, we used chronic active B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma as a model system to establish a computational framework to optimize combinatorial therapy in silico. We constructed a detailed kinetic model of the BCR signaling network, which captured the known complex cross-talk between the NFκB, ERK, and AKT pathways and multiple feedback loops. Combining this signaling model with a data-derived tumor growth model, we predicted viability responses of many single drug and drug combinations in agreement with experimental data. Under this framework, we exhaustively predicted and ranked the efficacy and synergism of all possible combinatorial inhibitions of eleven currently targetable kinases in the BCR signaling network. Ultimately, our work establishes a detailed kinetic model of the core BCR signaling network and provides the means to explore the large space of possible drug combinations. Cancer Res; 77(8); 1818–30. ©2017 AACR.
HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells
Authors: Zhu Shan , Zhang Qiuhong , Sun Xiaofan , Zeh Herbert J. , Lotze Michael T. , Kang Rui , Tang Daolin 
Published: January 2017

Abstract
Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here, we show that heatshock 70-kDa protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted in the induction of HSPA5, which in turn bound glutathione peroxidase 4 (GPX4) and protected against GPX4 protein degradation and subsequent lipid peroxidation. Importantly, the HSPA5–GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacologic inhibition of the HSPA5–GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosis in vitro and in both subcutaneous and orthotopic animal models of PDAC. Collectively, these findings identify a novel role of HSPA5 in ferroptosis and suggest a potential therapeutic strategy for overcoming gemcitabine resistance. Cancer Res; 77(8); 2064–77. ©2017 AACR.
CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer
Authors: Alfaqih Mahmoud A. , Nelson Erik R. , Liu Wen , Safi Rachid , Jasper Jeffery S. , Macias Everardo , Geradts Joseph , Thompson J. Will , Dubois Laura G. , Freeman Michael R. , Chang Ching-yi , Chi Jen-Tsan , McDonnell Donald P. , Freedland Stephen J. 
Published: January 2017

Abstract
In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis. Cancer Res; 77(7); 1662–73. ©2017 AACR.
Cellular Model of Colon Cancer Progression Reveals Signatures of mRNAs, miRNA, lncRNAs, and Epigenetic Modifications Associated with Metastasis
Authors: Rokavec Matjaz , Horst David , Hermeking Heiko 
Published: January 2017

Abstract
Here, we developed and comprehensively characterized a cellular model of colon cancer progression consisting of four defined derivatives of a colon cancer cell line that resulted from consecutive epithelial–mesenchymal and mesenchymal–epithelial transitions (EMT/MET) and phenotypically recapitulate the metastatic cascade. Initial EMT was induced by prolonged exposure to IL6, a cytokine also generated by the tumor-stroma. Genome-wide characterization of transcriptional (mRNA, miRNA, and lncRNA) and epigenetic (DNA methylation, H3K4me3, H3K79me3, and H3K27me3 histone modifications) profiles of the cell derivatives, combined with correlative analyses of expression, methylation, and clinical data from the TCGA-COAD database gave insights into the molecular basis of their phenotypic changes. The signatures characterizing invasive, mesenchymal-like cell states as well as the metastases-derived epithelial-like state showed significant association with metastasis, positive nodal status, and poor survival of colon cancer patients. Global hypomethylation of gene-regulatory regions was observed during tumor progression, with the lowest degree of methylation present in cells isolated from metastases. Upregulation of an axon-guidance–related gene signature was the most significant feature of metastatic tumor cells and was also found in primary tumors from colon cancer patients with distant metastases. Furthermore, the microRNAs miR-99a, miR-100, and miR-125b showed elevated expression in mesenchymal-like cells, associated with poor survival, and promoted migration and invasion. Finally, elevated expression of H19 lncRNA due to promoter demethylation was observed in cells isolated from metastases and was associated with poor survival of colon cancer patients. In the future, our results may be further exploited for the discovery and evaluation of novel metastasis-associated mechanisms and biomarkers. Cancer Res; 77(8); 1854–67. ©2017 AACR.
Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex
Authors: Rozovski Uri , Harris David M. , Li Ping , Liu Zhiming , Jain Preetesh , Veletic Ivo , Ferrajoli Alessandra , Burger Jan , O'Brien Susan , Bose Prithviraj , Thompson Philip , Jain Nitin , Wierda William , Keating Michael J. , Estrov Zeev 
Published: January 2017

AbstractIn chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that coimmunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that CD5 and BLNK coexpressed in CLL, but not in normal B- or T cells, are required for STAT3 phosphorylation. To elucidate the relationship of CD5 and BLNK to CK2 and STAT3, STAT3 was immunoprecipitated from CLL cells, and CK2, CD5, and BLNK were detected in the immunoprecipitate. Conversely, STAT3, CD5, and BLNK were in the immunoprecipitate of CLL cells immunoprecipitated with CK2 antibodies. Furthermore, siRNA knockdown of CD5 or BLNK, or treatment with CD5-neutralizing antibodies significantly reduced the levels of serine pSTAT3 in CLL cells. Finally, confocal microscopy determined that CD5 is cell membrane bound, and fractionation studies revealed that the CK2/CD5/BLNK/STAT3 complex remains in the cytoplasm, whereas serine pSTAT3 is shuttled to the nucleus.Implications: These data show that the cellular proteins CK2, CD5, and BLNK are required for constitutive phosphorylation of STAT3 in CLL. Whether this protein complex phosphorylates other proteins or inhibiting its activity would have clinical benefit in patients has yet to be determined. Mol Cancer Res; 15(5); 610–8. ©2017 AACR.
Impact of Ultrafiltration on Serum Sodium Homeostasis and its Clinical Implication in Patients With Acute Heart Failure, Congestion, and Worsening Renal Function
Authors: Kitai Takeshi , Grodin Justin L. , Kim Yong-Hyun , Tang W.H. Wilson 
Published: January 2017

Background—
The relationship between changes in serum sodium with clinical events in acute heart failure patients using different decongestive events has not been investigated. This study aimed to describe changes in serum sodium levels during decongestion therapy in patients receiving stepped pharmacological therapy versus ultrafiltration.

Methods and Results—

We studied 188 patients who were enrolled in the CARRESS-HF trial (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Treatment-induced hyponatremia was defined as admission normonatremia (≥135 mEq/L) with a subsequent decrease (<135 mEq/L) during hospitalization. Patients treated with ultrafiltration had significantly lower sodium levels than those with conventional treatment at days 1, 4, and 7 (all
P
<0.01), whereas those at day 30 were similar between the groups. Changes in sodium levels in patients with ultrafiltration were negatively correlated to those in serum creatinine and plasma renin activity. The incidence of treatment-induced hyponatremia was significantly higher in the ultrafiltration group than those receiving conventional treatment (
P
=0.002). Although patients with discharge hyponatremia had a higher risk for composite end point of all-cause death, rehospitalization, or unscheduled hospital visit in comparison to those without (adjusted hazard ratio, 2.01; 95% confidence interval, 1.09–3.70;
P
=0.025), the risk was comparable between patients with treatment-induced hyponatremia and those who did not experience any hyponatremia (adjusted hazard ratio, 0.99; 95% confidence interval, 0.50–1.96;
P
=0.99).

Conclusions—
Fluid removal by ultrafiltration was associated with a decrease in serum sodium levels compared with diuretic treatment but returned to baseline levels at day 30. Discharge hyponatremia but not treatment-induced hyponatremia was associated with worse clinical outcomes.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00608491.
Risk Factors of Subacute Thrombosis After Intracranial Stenting for Symptomatic Intracranial Arterial Stenosis
Authors: Sun Xuan , Tong Xu , Lo Wai Ting , Mo Dapeng , Gao Feng , Ma Ning , Wang Bo , Miao Zhongrong 
Published: January 2017

Background and Purpose—
We aimed to explore the risk factors of subacute thrombosis (SAT) after intracranial stenting for patients with symptomatic intracranial arterial stenosis.

Methods—
From January to December 2013, all symptomatic intracranial arterial stenosis patients who underwent intracranial stenting in Beijing Tiantan Hospital were prospectively registered into this study. Baseline clinical features and operative data were compared in patients who developed SAT with those who did not. Binary logistic regression model was used to determine the risk factors associated with SAT.

Results—
Of the 221 patients enrolled, 9 (4.1%) cases had SAT 2 to 8 days after stenting. Binary logistic analysis showed that SAT was related with tandem stenting (odds ratio [OR], 11.278; 95% confidence interval [CI], 2.422–52.519) and antiplatelet resistance (aspirin resistance: OR, 6.267; 95% CI, 1.574–24.952; clopidogrel resistance: OR, 15.526; 95% CI, 3.105–77.626; aspirin and clopidogrel resistance: OR, 12.246; 95% CI, 2.932–51.147; and aspirin or clopidogrel resistance: OR, 11.340; 95% CI, 2.282–56.344).

Conclusions—
Tandem stenting and antiplatelet resistance might contribute to the development of SAT after intracranial stenting in patients with symptomatic intracranial arterial stenosis.
Patient safety is not compromised by excluding microscopic examination of negative urine dipstick
Authors: Miler Marijana , Nikolac Nora 
Published: January 2017

Background Microscopic examination of samples with negative dipstick results is not necessary. The aims of this study were to: (i) assess the risk of excluding urine sediment examination with negative dipstick results and (ii) calculate time savings by introducing this process. Methods The risk analysis was done for samples with negative urine dipstick and positive sediment findings. Possible missed elements in sediment were defined as 21 errors. Time saving was calculated as average time for preparation and examination sediments. Data were presented as counts and percentages. Results Out of 2997 samples, negative dipstick results were reported for 926 (30.6%) samples, out of which, microscopic examinations were positive for 527 (17.6%) samples. 18/21 errors were detected, with missing <5 squamous epithelial cells (SQEC) and bacteria 1+ as the most frequent ones (22.7% and 22.4%, respectively). Errors with the intermediate risk for patients were missing to report: ≥5 SQEC, ≥5 transitional epithelial cells, ≥10 hyaline casts (11.9%, 0.21%, 0.32%, respectively). Errors associated with high risk were not detected. Estimated total time saving is more than 25 h/month. Conclusions Microscopic examination of urine samples with negative dipstick results can be excluded without risk for patients and can result with considerable time savings.
Criterion validity of a home health aide's algorithm for recommending bathroom equipment
Authors: Guay Manon , Desrosiers Johanne , Dubois Marie-France 
Published: January 2017

Background Occupational therapists are experts at adapting bathroom environments. However, to increase access to services, the algorithm “Préalables aux soins d'hygiène” (French for “Prerequisites for bathing care”) has been developed to be used by trained home health aides to recommend bathroom equipment. Purpose The purpose of this study was to assess the criterion validity of the algorithm by measuring the level of agreement between an occupational therapist's recommendations (gold standard) and those made by four home health aides using the algorithm. Methods Community-living adults with bathing difficulties (n = 96) were visited by both types of evaluators. Findings Home health aides correctly identified clinical situations in which they should feel confident about their ability (sensitivity: 96%, specificity: 69%) and, apart from type of bathing seat (Kw = 0.63 [0.52; 0.75]), agreement between recommendations varied from substantial to almost perfect (△≥0.72). Implications Results increase confidencein the algorithm, but other studies are needed to ensure population safety and fulfil the occupational therapist's obligations.