bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathophysiology of exercise intolerance in chronic diseases: the role of diminished cardiac performance in mitochondrial and heart failure patients
Authors: McCoy Jodi , Bates Matthew , Eggett Christopher , Siervo Mario , Cassidy Sophie , Newman Jane , Moore Sarah A , Gorman Grainne , Trenell Michael I , Velicki Lazar , Seferovic Petar M , Cleland John G F , MacGowan Guy A , Turnbull Doug M , Jakovljevic Djordje G 
Published: July 2017

ObjectiveExercise intolerance is a clinical hallmark of chronic conditions. The present study determined pathophysiological mechanisms of exercise intolerance in cardiovascular, neuromuscular, and metabolic disorders.MethodsIn a prospective cross-sectional observational study 152 patients (heart failure reduced ejection fraction, n=32; stroke, n=34; mitochondrial disease, n=28; type two diabetes, n=28; and healthy controls, n=30) performed cardiopulmonary exercise testing with metabolic and haemodynamic measurements. Peak exercise O2consumption and cardiac power output were measures of exercise tolerance and cardiac performance.ResultsExercise tolerance was significantly diminished in patients compared with controls (ie, by 45% stroke, 39% mitochondria disease, and 33% diabetes and heart failure, p<0.05). Cardiac performance was only significantly reduced in heart failure (due to reduced heart rate, stroke volume, and blood pressure) and mitochondrial patients (due reduced stroke volume) compared with controls (ie, by 53% and 26%, p<0.05). Ability of skeletal muscles to extract oxygen (ie, arterial-venous O2difference) was diminished in mitochondrial, stroke, and diabetes patients (by 24%, 22%, and 18%, p<0.05), but increased by 21% in heart failure (p<0.05) compared with controls. Cardiac output explained 65% and 51% of the variance in peak O2consumption (p<0.01) in heart failure and mitochondrial patients, whereas arterial-venous O2difference explained 69% (p<0.01) of variance in peak O2consumption in diabetes, and 65% and 48% in stroke and mitochondrial patients (p<0.01).ConclusionsDifferent mechanisms explain exercise intolerance in patients with heart failure, mitochondrial dysfunction, stroke and diabetes. Their better understanding may improve management of patients, their stress tolerance and quality of life.
Rituximab in early systemic sclerosis
Authors: Boonstra Maaike , Meijs Jessica , Dorjée Annemarie L , Marsan Nina Ajmone , Schouffoer Anne , Ninaber Maarten K , Quint Koen D , Bonte-Mineur Femke , Huizinga Tom W J , Scherer Hans U , de Vries-Bouwstra Jeska K 
Published: July 2017

Objectives(1) Hypothesis testing of the potency of rituximab (RTX) in preventing fibrotic complications and (2) assessing acceptability and feasibility of RTX in early systemic sclerosis (SSc).MethodsA small, 24-month, randomised, double-blind, placebo-controlled, single-centre trial in patients with SSc diagnosed <2 years was conducted. Patients received RTX or placebo infusions at t=0, t=15 days and t=6 months. Patients were clinically evaluated every 3 months, with lung function tests and high-resolution CT every other visit. Skin biopsies were taken at baseline and month 3. Immunophenotyping of peripheral blood mononuclear cells was performed at every visit, except at months 9 and 18. Adverse events, course of skin and pulmonary involvement and B cell populations in skin and peripheral blood were evaluated.ResultsIn total 16, patients (rituximab n=8, placebo n=8) were included. Twelve patients had diffuse cutaneous SSc. Eighty-eight adverse events (RTX n=53, placebo n=35, p=0.22) and 11 serious adverse events (RTX n=7, placebo n=4, p=0.36) occurred. No unexpected RTX-related events were observed. Mean skin score over time did not differ between the groups. Over time, forced vital capacity and extent of lung involvement slightly improved with RTX, but this difference was insignificant. In peripheral blood B cells depletion was demonstrated.ConclusionsNo unexpected safety issues were observed with RTX in early SSc. Although this small trial could not confirm or reject potential efficacy of RTX in these patients, future placebo-controlled trials are warranted, specifically in the subgroup of patients with pulmonary involvement.Trial registration numberEudraCT 2008-07180-16; Results.
Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis
Authors: Akbar Moeed , Gilchrist Derek S , Kitson Susan M , Nelis Briana , Crowe Lindsay A N , Garcia-Melchor Emma , Reilly James H , Kerr Shauna C , Murrell George A C , McInnes Iain B , Millar Neal L 
Published: July 2017

ObjectivesTo seek evidence of the danger molecule, high-mobility group protein B1 (HMGB1) expression in human tendinopathy and thereafter, to explore mechanisms where HMGB1 may regulate inflammatory mediators and matrix regulation in human tendinopathy.MethodsTorn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from patients undergoing arthroscopic stabilisation surgery. Markers of inflammation and HMGB1 were quantified by reverse transcriptase PCR (RT-PCR) and immunohistochemistry. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon anterior cruciate ligament reconstruction and used through passage 3. In vitro effects of recombinant HMGB1 on tenocyte matrix and inflammatory potential were measured using quantitative RT-PCR, ELISA and immunohistochemistry staining.ResultsTendinopathic tissues demonstrated significantly increased levels of the danger molecule HMGB1 compared with control tissues with early tendinopathy tissue showing the greatest expression. The addition of recombinant human HMGB1 to tenocytes led to significant increase in expression of a number of inflammatory mediators, including interleukin 1 beta (IL-1β), IL-6, IL-33, CCL2 and CXCL12, in vitro. Further analysis demonstrated rhHMGB1 treatment resulted in increased expression of genes involved in matrix remodelling. Significant increases were observed in Col3, Tenascin-C and Decorin. Moreover, blocking HMGB1 signalling via toll-like receptor 4 (TLR4) silencing reversed these key inflammatory and matrix changes.ConclusionHMGB1 is present in human tendinopathy and can regulate inflammatory cytokines and matrix changes. We propose HMGB1 as a mediator driving the inflammatory/matrix crosstalk and manipulation of the HMGB1/TLR4 axis may offer novel therapeutic approaches targeting inflammatory mechanisms in the management of human tendon disorders.
Crustal fluid flow in hot continental extension: tectonic framework of geothermal areas and mineral deposits in western Anatolia
Authors: Gessner Klaus , Markwitz Vanessa , Güngör Talip 
Published: July 2017

Abstract
Lithospheric thinning and crustal extension have shaped the Alpine orogen in western Anatolia since the late Oligocene, resulting in the denudation of one of Earth's largest metamorphic core complexes, the Menderes Massif. We review locations and characteristics of geothermal fields and of Miocene mineral deposits in the context of crustal structure and geodynamic processes. Thermal spring locations show a close spatial association with active fault zones; the largest geothermal areas are located in the widest graben and at fault intersections, but show little relation to volcanic activity. During the first stage of tectonic denudation in the Miocene, epithermal, porphyry-type gold and structurally controlled base-metal deposits formed synchronously with K-rich volcanic and plutonic complexes in the northern Menderes Massif. Depositional environments favoured the formation of lignite, sedimentary uranium and borate deposits. Throughout this phase of extension in a hot continental setting, secondary porosity caused by brittle faulting of metamorphic basement rocks provided the key pathways for fluids and magmas. Although the Menderes Massif has remained in a similar position relative to active plate boundaries from the Miocene to the present, three significant changes in subcontinental mantle dynamics affected the nature of hydrothermal flow. First, the partial removal of lithospheric mantle changed the primary source component of magmatic rocks and metals from metasomatized lithosphere mantle to asthenospheric mantle. Secondly, surface uplift and progressive crustal extension led to segmentation of the Miocene land surface along NNE–SSW- and east–west-orientated fault zones, which changed the overall structural control on crustal permeability. Finally, hydrothermal flow changed from locally magmatic driven, to focused flow of topographically and thermally driven fluids in the crust, with high background heat flow caused by regional upwelling of the asthenosphere. The Menderes Massif is a continental tectonic domain that has experienced rapid thinning of lithospheric mantle and crustal extension in an overall convergent plate tectonic setting. The tectonic and geodynamic framework for evolving hydrothermal activity in western Anatolia may be applicable to other ore-forming systems in hot, extending continental crust in Earth's history.
Intracoronary delivery of recombinant TIMP-3 after myocardial infarction: effects on myocardial remodeling and function
Authors: Barlow Shayne C. , Doviak Heather , Jacobs Julia , Freeburg Lisa A. , Perreault Paige E. , Zellars Kia N. , Moreau Karen , Villacreses Camila F. , Smith Stephen , Khakoo Aarif Y. , Lee TaeWeon , Spinale Francis G. 
Published: July 2017

Ischemia-reperfusion (IR) and myocardial infarction (MI) cause adverse left ventricular (LV) remodeling and heart failure and are facilitated by an imbalance in matrix metalloproteinase (MMP) activation and the endogenous tissue inhibitors of metalloproteinase (TIMPs). We have identified that myocardial injections of recombinant TIMP-3 (rTIMP-3; human full length) can interrupt post-MI remodeling. However, whether and to what degree intracoronary delivery of rTIMP-3 post-IR is feasible and effective remained to be established. Pigs (25 kg) underwent coronary catheterization and balloon occlusion of the left anterior descending coronary artery (LAD) for 90 min whereby at the final 4 min, rTIMP-3 (30 mg, n = 9) or saline was infused in the distal LAD. LV echocardiography was performed at 3–28 days post-IR, and LV ejection fraction (EF) and LV end-diastolic volume were measured. LV EF fell and LV end-diastolic volume increased from baseline (pre-IR) values (66 ± 1% and 40 ± 1 ml, respectively, means ± standard deviation) in both groups; however, the extent of LV dilation was reduced in the rTIMP-3 group by 40% at 28 days post-IR ( P < 0.05) and the fall in LV EF was attenuated. Despite equivalent plasma troponin levels (14 ± 3 ng/ml), computed MI size at 28 days was reduced by over 45% in the rTIMP-3 group ( P < 0.05), indicating that rTIMP-3 treatment abrogated MI expansion post-IR. Plasma NH2-terminal pro-brain natriuretic peptide levels, an index of heart failure progression, were reduced by 25% in the rTIMP-3 group compared with MI saline values ( P < 0.05). Although the imbalance between MMPs and TIMPs has been recognized as a contributory factor for post-MI remodeling, therapeutic strategies targeting this imbalance have not been forthcoming. This study is the first to demonstrate that a relevant delivery approach (intracoronary) using rTIMP can alter the course of post-MI remodeling.NEW & NOTEWORTHY Myocardial ischemia and reperfusion injury remain significant causes of morbidity and mortality whereby alterations in the balance between matrix metalloproteinase and tissue inhibitor of metalloproteinase have been identified as contributory biological mechanisms. This novel translational study advances the concept of targeted delivery of recombinant proteins to modify adverse myocardial remodeling in ischemia-reperfusion injury.
Visualization of three pathways for macromolecule transport across cultured endothelium and their modification by flow
Authors: Ghim Mean , Alpresa Paola , Yang Sung-Wook , Braakman Sietse T. , Gray Stephen G. , Sherwin Spencer J. , van Reeuwijk Maarten , Weinberg Peter D. 
Published: July 2017

Transport of macromolecules across vascular endothelium and its modification by fluid mechanical forces are important for normal tissue function and in the development of atherosclerosis. However, the routes by which macromolecules cross endothelium, the hemodynamic stresses that maintain endothelial physiology or trigger disease, and the dependence of transendothelial transport on hemodynamic stresses are controversial. We visualized pathways for macromolecule transport and determined the effect on these pathways of different types of flow. Endothelial monolayers were cultured under static conditions or on an orbital shaker producing different flow profiles in different parts of the wells. Fluorescent tracers that bound to the substrate after crossing the endothelium were used to identify transport pathways. Maps of tracer distribution were compared with numerical simulations of flow to determine effects of different shear stress metrics on permeability. Albumin-sized tracers dominantly crossed the cultured endothelium via junctions between neighboring cells, high-density lipoprotein-sized tracers crossed at tricellular junctions, and low-density lipoprotein-sized tracers crossed through cells. Cells aligned close to the angle that minimized shear stresses across their long axis. The rate of paracellular transport under flow correlated with the magnitude of these minimized transverse stresses, whereas transport across cells was uniformly reduced by all types of flow. These results contradict the long-standing two-pore theory of solute transport across microvessel walls and the consensus view that endothelial cells align with the mean shear vector. They suggest that endothelial cells minimize transverse shear, supporting its postulated proatherogenic role. Preliminary data show that similar tracer techniques are practicable in vivo.NEW & NOTEWORTHY Solutes of increasing size crossed cultured endothelium through intercellular junctions, through tricellular junctions, or transcellularly. Cells aligned to minimize the shear stress acting across their long axis. Paracellular transport correlated with the level of this minimized shear, but transcellular transport was reduced uniformly by flow regardless of the shear profile.
Spi-B–Mediated Silencing of Claudin-2 Promotes Early Dissemination of Lung Cancer Cells from Primary Tumors
Authors: Du Wei , Xu Xing , Niu Qing , Zhang Xuexi , Wei Yiliang , Wang Ziqiao , Zhang Wei , Yan Jun , Ru Yongxin , Fu Zheng , Li Xiaobo , Jiang Yuan , Ma Zhenyi , Zhang Zhenfa , Yao Zhi , Liu Zhe 
Published: July 2017

AbstractDissociation from epithelial sheets and invasion through the surrounding stroma are critical early events during epithelial cancer metastasis. Here we find that a lymphocyte lineage–restricted transcription factor, Spi-B, is frequently expressed in human lung cancer tissues. The Spi-B–expressing cancer cells coexpressed vimentin but repressed E-cadherin and exhibited invasive behavior. Increased Spi-B expression was associated with tumor grade, lymphatic metastasis, and short overall survival. Mechanistically, Spi-B disrupted intercellular junctions and enhanced invasiveness by reconfiguring the chromatin structure of the tight junction gene claudin-2 (CLDN2) and repressing its transcription. These data suggest that Spi-B participates in mesenchymal invasion, linking epithelial cancer metastasis with a lymphatic transcriptional program. Cancer Res; 77(18); 4809–22. ©2017 AACR.
NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas
Authors: Su Xiaoping , Zhang Jianping , Mouawad Roger , Compérat Eva , Rouprêt Morgan , Allanic Frederick , Parra Jérôme , Bitker Marc-Olivier , Thompson Erika J. , Gowrishankar Banumathy , Houldsworth Jane , Weinstein John N. , Tost Jorg , Broom Bradley M. , Khayat David , Spano Jean-Philippe , Tannir Nizar M. , Malouf Gabriel G. 
Published: July 2017

Abstract
Extensive dysregulation of chromatin-modifying genes in clear cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the cross-talk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear cell CpG island methylator phenotype (C-CIMP) subgroup associated with promoter methylation of VEGF genes (FLT4, FLT1, and KDR). C-CIMP was furthermore characterized by silencing of genes related to vasculature development. Through an integrative analysis, we discovered frequent silencing of the histone H3 K36 methyltransferase NSD1 as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC. Notably, tumors harboring NSD1 methylation were of higher grade and stage in different ccRCC datasets. NSD1 promoter methylation correlated with SETD2 somatic mutations across and within spatially distinct regions of primary ccRCC tumors. ccRCC harboring epigenetic silencing of NSD1 displayed a specific genome-wide methylome signature consistent with the NSD1 mutation methylome signature observed in Sotos syndrome. Thus, we concluded that epigenetic silencing of genes involved in angiogenesis is a hallmark of the methylator phenotype in ccRCC, implying a convergence toward loss of function of epigenetic writers of the H3K36 histone mark as a root feature of aggressive ccRCC. Cancer Res; 77(18); 4835–45. ©2017 AACR.
Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPβ Signaling
Authors: Yin Jinlong , Oh Young Taek , Kim Jeong-Yub , Kim Sung Soo , Choi Eunji , Kim Tae Hoon , Hong Jun Hee , Chang Nakho , Cho Hee Jin , Sa Jason K. , Kim Jeong Cheol , Kwon Hyung Joon , Park Saewhan , Lin Weiwei , Nakano Ichiro , Gwak Ho-Shin , Yoo Heon , Lee Seung-Hoon , Lee Jeongwu , Kim Jong Heon , Kim Soo-Youl , Nam Do-Hyun , Park Myung-Jin , Park Jong Bae 
Published: July 2017

Abstract
Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage–inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973–84. ©2017 AACR.
Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma
Authors: Liu Yan , Li Yuyang , Wang Xiaoen , Liu Feiyang , Gao Peng , Quinn Max M. , Li Fei , Merlino Ashley A. , Benes Cyril , Liu Qingsong , Gray Nathanael S. , Wong Kwok-Kin 
Published: July 2017

Abstract
Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1–induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas. Cancer Res; 77(18); 5068–76. ©2017 AACR.
Integrating Models to Quantify Environment-Mediated Drug Resistance
Authors: Picco Noemi , Sahai Erik , Maini Philip K. , Anderson Alexander R.A. 
Published: July 2017

Abstract
Drug resistance is the single most important driver of cancer treatment failure for modern targeted therapies, and the dialog between tumor and stroma has been shown to modulate the response to molecularly targeted therapies through proliferative and survival signaling. In this work, we investigate interactions between a growing tumor and its surrounding stroma and their role in facilitating the emergence of drug resistance. We used mathematical modeling as a theoretical framework to bridge between experimental models and scales, with the aim of separating intrinsic and extrinsic components of resistance in BRAF-mutated melanoma; the model describes tumor–stroma dynamics both with and without treatment. Integration of experimental data into our model revealed significant variation in either the intensity of stromal promotion or intrinsic tissue carrying capacity across animal replicates. Cancer Res; 77(19); 5409–18. ©2017 AACR.
Adipose Progenitor Cell Secretion of GM-CSF and MMP9 Promotes a Stromal and Immunological Microenvironment That Supports Breast Cancer Progression
Authors: Reggiani Francesca , Labanca Valentina , Mancuso Patrizia , Rabascio Cristina , Talarico Giovanna , Orecchioni Stefania , Manconi Andrea , Bertolini Francesco 
Published: July 2017

AbstractA cell population with progenitor-like phenotype (CD45-CD34+) resident in human white adipose tissue (WAT) is known to promote the progression of local and metastatic breast cancer and angiogenesis. However, the molecular mechanisms of the interaction have not been elucidated. In this study, we identified two proteins that were significantly upregulated in WAT-derived progenitors after coculture with breast cancer: granulocyte macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase 9 (MMP9). These proteins were released by WAT progenitors in xenograft and transgenic breast cancer models. GM-CSF was identified as an upstream modulator. Breast cancer–derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the protumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. Combined GM-CSF neutralization and MMP9 inhibition synergistically reduced angiogenesis and tumor progression. High-dose metformin inhibited GM-CSF and MMP9 release from WAT progenitors in in vitro and xenograft models. In obese syngeneic mice, metformin treatment mimicked the effects observed with GM-CSF neutralization and MMP9 inhibition, suggesting these proteins as new targets for metformin. These findings support the hypothesis that GM-CSF and MMP9 promote the protumorigenic effect of WAT progenitors on local and metastatic breast cancer. Cancer Res; 77(18); 5169–82. ©2017 AACR.