bluuebunny/crossref_metadata_2025 huggingface dataset:
Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders
Authors: Vachin Pauline , Adda-Herzog Elodie , Chalouhi Gihad , Elie Caroline , Rio Marlène , Rondeau Sophie , Gigarel Nadine , Jabot Hanin Fabienne , Monnot Sophie , Borghese Roxana , Bengoa Joana , Ville Yves , Rotig Agnes , Munnich Arnold , Bonnefont Jean-Paul , Steffann Julie
Published: July 2017

Background

Mitochondrial DNA (mtDNA) disorders have a high clinical variability, mainly explained by variation of the mutant load across tissues. The high recurrence risk of these serious diseases commonly results in requests from at-risk couples for prenatal diagnosis (PND), based on determination of the mutant load on a chorionic villous sample (CVS). Such procedures are hampered by the lack of data regarding mtDNA segregation in the placenta.

The objectives of this report were to determine whether mutant loads (1) are homogeneously distributed across the whole placentas, (2) correlate with those in amniocytes and cord blood cells and (3) correlate with the mtDNA copy number.

Methods

We collected 11 whole placentas carrying various mtDNA mutations (m.3243A>G, m.8344A>G, m.8993T>G, m.9185T>C and m.10197G>A) and, when possible, corresponding amniotic fluid samples (AFSs) and cord blood samples. We measured mutant loads in multiple samples from each placenta (n= 6–37), amniocytes and cord blood cells, as well as total mtDNA content in placenta samples.

Results

Load distribution was homogeneous at the sample level when average mutant load was low (<20%) or high (>80%) at the whole placenta level. By contrast, a marked heterogeneity was observed (up to 43%) in the intermediate range (20%–80%), the closer it was to 40%–50% the mutant load, the wider the distribution. Mutant loads were found to be similar in amniocytes and cord blood cells, at variance with placenta samples. mtDNA content correlated to mutant load in m.3243A>G placentas only.

Conclusion

These data indicate that (1) mutant load determined from CVS has to be interpreted with caution for PND of some mtDNA disorders and should be associated with/substituted by a mutant load measurement on amniocytes; (2) the m.3243A>G mutation behaves differently from other mtDNA mutations with respect to the impact on mtDNA copy number, as previously shown in human preimplantation embryogenesis.
Cardiovascular risk profiles in a lupus cohort: what do different calculators tell us?
Authors: Boulos Daniel , Koelmeyer Rachel L , Morand Eric F , Hoi Alberta Y
Published: July 2017

Background

Cardiovascular disease (CVD) is the leading cause of death worldwide and this risk is increased in patients with SLE who may not conform to traditional cardiovascular risk profiles.

Aims

To determine the prevalence of high CVD risk among patients with SLE calculated using different risk calculators, and to characterise those identified as high risk.

Methods

A cross-sectional analysis to estimate CVD risk using the Framingham Risk Equation (Framingham score) and an SLE-specific CVD risk equation (SLE score) was undertaken using data from a single centre cohort. The characteristics of patients identified as ‘high risk’ by the SLE score only (the ‘missed group’) were compared with those identified by the Framingham score (the ‘conventional group’).

Results

146 patients were included; 22 (15%) and 44 (30%) were determined to be at ‘high risk’ based on the Framingham and SLE scores, respectively. Patients in the ‘missed group’ were less likely to have traditional risk factors and were more likely to be female (81% vs 50%; p=0.03), younger (mean age 54 vs 69 years p<0.01) and have lower systolic blood pressure (132 vs 143 mm Hg; p=0.05). Of those deemed high risk, only a minority were treated to target blood pressure and lipid levels.

Conclusions

A large proportion of patients with SLE could be re-classified as high risk using a formula that incorporates SLE disease-related parameters. These patients have different profiles to those identified using a conventional risk model. Optimal CVD risk assessment and management warrants further attention in SLE.
Strong viral associations with SLE among Filipinos
Authors: Vista Evan S , Weisman Michael H , Ishimori Mariko L , Chen Hua , Bourn Rebecka L , Bruner Ben F , Hamijoyo Laniyati , Tanangunan Robelle D , Gal Noga J , Robertson Julie M , Harley John B , Guthridge Joel M , Navarra Sandra V , James Judith A
Published: July 2017

Objectives

Epstein-Barr virus (EBV) is considered an important environmental factor in SLE aetiology, but the relationship between SLE and EBV in the Filipino population is unknown. We tested associations between SLE, lupus-associated autoantibodies and seropositivity for EBV and other herpes viruses in the Filipino population.

Methods

Sera from Filipino patients with SLE (n=233), unaffected first-degree relatives (FDRs, n=543) and unrelated controls (n=221) were tested for antibodies against EBV, cytomegalovirus (CMV) and herpes simplex viruses (HSV-1 and HSV-2) by standardised ELISAs. Humoral specificity against EBV nuclear antigen (EBNA)-1 was compared by solid-phase epitope mapping. Autoantibodies were detected by a bead-based multiplex assay. Results were analysed by Fisher's exact test, Student's t-test, χ2test and one-way analysis of variance, as appropriate for the question.

Results

Filipino patients with SLE had increased seroprevalence and elevated antibody concentrations against EBV viral capsid antigen (EBV-VCA), CMV, HSV-1 and HSV-2 compared with unrelated controls (p<0.05). Seropositivity for anti-EBV early antigen (EA), a marker of EBV reactivation, was dramatically increased in patients with SLE compared with unrelated controls (92.3% vs 40.4%; OR 17.15(95% CI 10.10, 30.66), p<0.0001) or unaffected FDRs (49.4%; OR 12.04(7.42, 20.74), p<0.0001), despite similar seroprevalence of EBV-VCA in patients and FDRs. In patients with SLE, EBV-EA seropositivity correlated with lupus-associated autoantibodies (p<0.001), most notably with autoantibodies against dsDNA, chromatin, Sm, SmRNP and RNP A (p<0.01). Patient and unrelated control sera reacted to the highly repetitive glycine and alanine domain of EBNA-1. An epitope spanning EBNA-1410-420was identified in sera of patients with SLE and showed limited binding by FDR and control sera.

Conclusions

Filipino patients with SLE have elevated prevalence and concentrations of antibodies against EBV, CMV, HSV-1 and HSV-2 antigens, along with altered anti-EBNA-1 specificities. EBV reactivation is more common among Filipino patients with SLE compared with healthy Filipinos and may contribute to SLE pathogenesis in this population.
Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE
Authors: Wirestam Lina , Frodlund Martina , Enocsson Helena , Skogh Thomas , Wetterö Jonas , Sjöwall Christopher
Published: July 2017

Objective

The variety of disease phenotypes among patients with SLE challenges the identification of new biomarkers reflecting disease activity and/or organ damage. Osteopontin (OPN) is an extracellular matrix protein with immunomodulating properties. Although raised levels have been reported, the pathogenic implications and clinical utility of OPN as a biomarker in SLE are far from clear. Thus, the aim of this study was to characterise OPN in SLE.

Methods

Sera from 240 well-characterised adult SLE cases classified according to the American College of Rheumatology (ACR) and/or the Systemic Lupus International Collaborating Clinics (SLICC) criteria, and 240 population-based controls were immunoassayed for OPN. The SLE Disease Activity Index 2000 (SLEDAI-2K) was used to evaluate disease activity and the SLICC/ACR Damage Index (SDI) to detect damage accrual.

Results

Serum OPN levels were in average raised fourfold in SLE cases compared with the controls (p<0.0001). OPN correlated with SLEDAI-2K, especially in patients with a disease duration of <12 months (r=0.666, p=0.028). OPN was highly associated with SDI (p<0.0001), especially in the renal (p<0.0001), cardiovascular (p<0.0001) and malignancy (p=0.012) domains. Finally, OPN associated with coherent antiphospholipid syndrome (APS; p=0.009), and both clinical and laboratory criteria of APS had significant positive impact on OPN levels.

Conclusions

In this cross-sectional study, circulating OPN correlates with disease activity in recent-onset SLE, reflects global organ damage and associates with APS. Longitudinal studies to dissect whether serum OPN also precedes and predicts future organ damage are most warranted.
Impact of balloon guide catheter on technical and clinical outcomes: a systematic review and meta-analysis
Authors: Brinjikji Waleed , Starke Robert M , Murad M Hassan , Fiorella David , Pereira Vitor M , Goyal Mayank , Kallmes David F
Published: July 2017

Background and purpose

Flow arrest with balloon guide catheters (BGCs) is becoming increasingly recognized as critical to optimizing patient outcomes for mechanical thrombectomy. We performed a systematic review and meta-analysis of the literature for studies that compared angiographic and clinical outcomes for patients who underwent mechanical thrombectomy with and without BGCs.

Materials and methods

In April 2017 a literature search on BGC and mechanical thrombectomy for stroke was performed. All studies included patients treated with and without BGCs using modern techniques (ie, stent retrievers). Using random effects meta-analysis, we evaluated the following outcomes: first-pass recanalization, Thrombolysis In Cerebral Infarction (TICI) 3 recanalization, TICI 2b/3 recanalization, favorable outcome (modified Rankin Scale (mRS) 0–2), mortality, and mean number of passes and procedure time.

Results

Five non-randomized studies of 2022 patients were included (1083 BGC group and 939 non-BGC group). Compared with the non-BGC group, patients treated with BGCs had higher odds of first-pass recanalization (OR 2.05, 95% CI 1.65 to 2.55), TICI 3 (OR 2.13, 95% CI 1.43 to 3.17), TICI 2b/3 (OR 1.54, 95% CI 1.21 to 1.97), and mRS 0–2 (OR 1.84, 95% CI 1.52 to 2.22). BGC-treated patients also had lower odds of mortality (OR 0.52, 95% CI 0.37 to 0.73) compared with non-BGC patients. The mean number of passes was significantly lower for BGC-treated patients (weighted mean difference −0.34, 95% CI−0.47 to −0.22). Mean procedure time was also significantly shorter for BGC-treated patients (weighted mean difference −7.7 min, 95% CI−9.0to −6.4).

Conclusions

Non-randomized studies suggest that BGC use during mechanical thrombectomy for acute ischemic stroke is associated with superior clinical and angiographic outcomes. Further randomized trials are needed to confirm the results of this study.
Balloon-assisted coil embolization and large stent delivery for cerebral aneurysms with a new generation of dual lumen balloons (Copernic 2L)
Authors: Guenego Adrien , Zerlauth Jean-Baptiste , Puccinelli Francesco , Hajdu Steven , Rotzinger David C , Zibold Felix , Piechowiak Eike I , Mordasini Pasquale , Gralla Jan , Dobrocky Tomas , Daniel Roy T , Chapot René , Mosimann Pascal J
Published: July 2017

Introduction

Dual coaxial lumen balloon microcatheters through which small stents can be delivered have recently been described. We report a series of a new type of dual lumen balloon catheter with a parallel lumen design enabling enhanced inflation and deflation properties through which larger stents may be deployed, including flow diverters (FD).

Methods

All aneurysms that were treated with a Copernic 2L (COP2L) dual lumen balloon catheter at our institution between February 2014 and December 2016 were assessed. Patient demographics, aneurysm characteristics, clinical and angiographic follow-up, as well as adverse events were analyzed.

Results

A total of 18 aneurysms in 16 patients (14 women) were treated with the COP2L. Mean maximal aneurysm diameter was 6.4 mm, mean neck size was 3.3 mm (min 1; max 6.3), and mean aneurysm height/width was 1.1 (min 0.5; max 2.1). The COP2L was used for balloon-remodeled coiling exclusively in 2 aneurysms; coiling and FD stenting in 8; coiling and braided stent delivery in 3; coiling, braided and FD stenting in 1; and FD stenting without coiling in 4 (stenting alone). The rate of Roy–Raymond 1 (complete occlusion) changed from 22% in the immediate postoperative period to 100% at 3 months (mean imaging follow-up 8.2 months). There were three technical complications (3/16, 18.7%), including a perforation and two thromboembolic asymptomatic events that were rapidly controlled with the COP2L. There was no immediate or delayed morbidity or mortality (modified Rankin Scale score 0–1 in 100% of patients).

Conclusion

The COP2L is a new type of dual lumen balloon catheter that may be useful for balloon and/or stent-assisted coiling of cerebral aneurysms. The same device can be used to deliver stents up to 4.5 mm and to optimize stent/wall apposition or serve as a life-saving tool in case of thromboembolic or hemorrhagic events. Long-term efficacy and safety need to be further assessed with larger case-controlled cohorts.
Exercise dose and all-cause mortality within extended cardiac rehabilitation: a cohort study
Authors: Taylor Claire , Tsakirides Costas , Moxon James , Moxon James W , Dudfield Michael , Witte Klaus , Ingle Lee , Carroll Sean
Published: July 2017

Aims

To investigate the relationship between exercise participation, exercise ‘dose’ expressed as metabolic equivalent (MET) hours (h) per week, and prognosis in individuals attending an extended, community-based exercise rehabilitation programme.

Methods

Cohort study of 435 participants undertaking exercise-based cardiac rehabilitation (CR) in Leeds, West Yorkshire, UK between 1994 and 2006, followed up to 1 November 2013. MET intensity of supervised exercise was estimated utilising serial submaximal exercise test results and corresponding exercise prescriptions. Programme participation was routinely monitored. Cox regression analysis including time-varying and propensity score adjustment was applied to identify predictors of long-term, all-cause mortality across exercise dose and programme duration groups.

Results

There were 133 events (31%) during a median follow-up of 14 years (range, 1.2 to 18.9 years). The significant univariate association between exercise dose and all-cause mortality was attenuated following multivariable adjustment for other predictors, including duration in the programme. Longer-term adherence to supervised exercise training (>36 months) was associated with a 33% lower mortality risk (multivariate-adjusted HR: 0.67; 95% CI: 0.47 to 0.97; p=0.033) compared with all lesser durations of CR (3, 12, 36 months), even after adjustment for baseline fitness, comorbidities and survivor bias.

Conclusion

Exercise dose (MET-h per week) appears less important than long-term adherence to supervised exercise for the reduction of long-term mortality risk. Extended, supervised CR programmes within the community may play a key role in promoting long-term exercise maintenance and other secondary prevention therapies for survival benefit.
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

Objective

Exercise intolerance is a clinical hallmark of chronic conditions. The present study determined pathophysiological mechanisms of exercise intolerance in cardiovascular, neuromuscular, and metabolic disorders.

Methods

In 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.

Results

Exercise 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).

Conclusions

Different 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).

Methods

A 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.

Results

In 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.

Conclusions

No 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 number

EudraCT 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

Objectives

To 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.

Methods

Torn 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.

Results

Tendinopathic 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.

Conclusion

HMGB1 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.
Biochemical and physiological parameters associated withTrypanosomaevansiprevalence in wild capybaras (Hydrochoerushydrochaeris)
Authors: Eberhardt A.T. , Beldomenico P.M. , Monje L.D. , Racca A.L.
Published: July 2017

Parasites can be detrimental to the health of wildlife populations and may negatively affect several aspects of the life history of their hosts. Investigating host health, therefore, is key to understanding important mechanisms of the host–parasite interaction at the individual and population levels. Recently, we reported a prevalence of 10% of Trypanosoma evansi Steel, 1884 in a population of capybaras (Hydrochoerus hydrochaeris (L., 1766)) from Esteros del Iberá, Argentina; however, the impact of T. evansi infection on capybaras is unknown. The aim of this study was to explore associations between T. evansi infection and biochemical and physiological parameters in wild capybaras using blood samples (n = 60) from a managed population of free-ranging capybaras from Esteros del Iberá. Infection by T. evansi was negatively associated with body condition, albumin, alpha-2 globulin concentrations, albumin/globulin ratio, and eosinophil counts, and it was positively associated with spleen index and gamma-globulin concentrations. These results suggest that T. evansi infection may pose a significant impact on the health of wild capybaras.
Hot bats go cold: heterothermy in neotropical bats
Authors: Czenze Zenon J. , Dunbar Miranda B.
Published: July 2017

Torpor is common in bats, but has historically been viewed as an energy-saving technique reserved for temperate and subarctic climates; however, torpor use is common across several tropical bat families. Central America hosts a great diversity of bats with approximately 150 species, yet data from this area are lacking compared with tropical Africa and Australia. We investigated thermoregulatory responses of bats from neotropical Belize and captured adult bats in the tropical forests of Lamanai Archeological Reserve, Belize. After a 12 h acclimation period, we recorded rectal temperature prior to and after exposing bats to an ambient temperature (Ta) of 7 °C for up to 2 h in an environmental chamber. All 11 species across four families expressed torpor to some degree upon exposure to cool temperatures. Individuals from Vespertilionidae defended the lowest resting body temperature (Tb) and showed the greatest decrease in Tb after acute exposure to low Ta. Our data help to establish a new spectrum of physiological ability for this group of mammals and shed light on the evolution of torpor and heterothermy. We show that energy conservation is important even in warm and energetically stable environmental conditions. Understanding how and why torpor is used in warm climates will help to better define paradigms in physiological ecology.
Costs and benefits of straight versus tortuous migration paths for Prairie Rattlesnakes (Crotalus viridis viridis) in seminatural and human-dominated landscapes
Authors: Martin A.E. , Jørgensen D. , Gates C.C.
Published: July 2017

An individual’s migration path shape should affect its fitness, because patchily distributed features (e.g., prey) are encountered more often on straight than tortuous paths. We hypothesized that Prairie Rattlesnakes (Crotalus viridis viridis (Rafinesque, 1818)) with straighter migration paths should have better body condition, because they encounter prey patches more frequently, and higher migration mortality, because they also encounter predators and hazardous human land uses more frequently, than individuals with tortuous paths. If true, then a straighter path should be favoured when the benefit (resource acquisition) outweighs the cost (mortality risk). Humans pose a significant mortality risk for migrants; thus, the cost of straight-line movement should increase relative to the benefit in more human-dominated landscapes, favouring more tortuous movements. We tested these hypotheses using data on the body condition, mortality, and migration movements of 25 female Prairie Rattlesnakes in one human-dominated and one seminatural landscape. As hypothesized, we found better body condition and higher migration mortality for snakes with straighter migration paths, and that snakes followed more tortuous paths in the human-dominated landscape. Although selection for tortuous movements may reduce rates of migration mortality in human-dominated landscapes, this may ultimately contribute to population declines if poorer body condition reduces overwinter survival or reproductive success.
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

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

Dissociation 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

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

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

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

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

A 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.
Connecting Cancer to Its Causes Requires Incorporation of Effects on Tissue Microenvironments
Authors: DeGregori James
Published: July 2017

In a recent article in Science, Tomasetti and colleagues present an expanded model for cancer risk, which they claim demonstrates the relative contribution of mutations caused by replication errors, environment, and heredity. The foundation of this model is the theory that the overwhelming driver of cancer risk is mutations. This perspective will present experimental evidence and evolutionary theory to challenge the basis of this underlying theory. An argument will be presented that the mutation-centric model of cancer suggests unrealistic solutions to cancer and distracts the research community from more promising approaches that consider tissue context. Cancer Res; 77(22); 6065–8. ©2017 AACR.
Protecting Privacy in Large Datasets—First We Assess the Risk; Then We Fuzzy the Data
Authors: Ursin Giske , Sen Sagar , Mottu Jean-Marie , Nygård Mari
Published: July 2017

Background: Privacy of information is an increasing concern with the availability of large amounts of data from many individuals. Even when access to data is heavily controlled, and the data shared with researchers contain no personal identifying information, there is a possibility of reidentifying individuals. To avoid reidentification, several anonymization protocols are available. These include categorizing variables into broader categories to ensure more than one individual in each category, such as k-anonymization, as well as protocols aimed at adding noise to the data. However, data custodians rarely assess reidentification risks.

Methods: We assessed the reidentification risk of a large realistic dataset based on screening data from over 5 million records on 0.9 million women in the Norwegian Cervical Cancer Screening Program, before and after we used old and new techniques of adding noise (fuzzification) of the data.

Results: Categorizing date variables (applying k-anonymization) substantially reduced the possibility of reidentification of individuals. Adding a random factor, such as a fuzzy factor used here, makes it even more difficult to reidentify specific individuals.

Conclusions: Our results show that simple techniques can substantially reduce the risk of reidentification.

Impact: Registry owners and large-scale data custodians should consider estimating and if necessary, reducing reidentification risks before sharing large datasets. Cancer Epidemiol Biomarkers Prev; 26(8); 1219–24. ©2017 AACR.
A Comparative Study on the WCRF International/University of Bristol Methodology for Systematic Reviews of Mechanisms Underpinning Exposure–Cancer Associations
Authors: Ertaylan Gökhan , Le Cornet Charlotte , van Roekel Eline H. , Jung Audrey Y. , Bours Martijn J.L. , Damms-Machado Antje , van den Brandt Piet A. , Schock Helena , de Kok Theo M. , Theys Jan , Arts Ilja C.W. , Kaaks Rudolf , Weijenberg Matty P. , Fortner Renée Turzanski
Published: July 2017

The World Cancer Research Fund (WCRF) International and the University of Bristol have developed a novel framework for providing an overview of mechanistic pathways and conducting a systematic literature review of the biologically plausible mechanisms underlying exposure–cancer associations. Two teams independently applied the two-stage framework on mechanisms underpinning the association between body fatness and breast cancer to test the framework feasibility and reproducibility as part of a WCRF-commissioned validation study. In stage I, a “hypothesis-free” approach was used to provide an overview of potential intermediate mechanisms between body fatness and breast cancer. Dissimilar rankings of potential mechanisms were observed between the two teams due to different applications of the framework. In stage II, a systematic review was conducted on the insulin-like growth factor 1 receptor (IGF1R) chosen as an intermediate mechanism. Although the studies included differed, both teams found inconclusive evidence for the body fatness–IGF1R association and modest evidence linking IGF1R to breast cancer, and therefore concluded that there is currently weak evidence for IGF1R as mechanism linking body fatness to breast cancer. The framework is a good starting point for conducting systematic reviews by integrating evidence from mechanistic studies on exposure–cancer associations. On the basis of our experience, we provide recommendations for future users. Cancer Epidemiol Biomarkers Prev; 26(11); 1583–94. ©2017 AACR.