bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesozoic structural evolution of the New Siberian Islands
Authors: Piepjohn Karsten , Lorenz Henning , Franke Dieter , Brandes Christian , von Gosen Werner , Gaedicke Christoph , Labrousse Loic , Sobolev Nikolay N. , Solobev Piotr , Suan Guillaume , Mrugalla Sabine , Talarico Franco , Tolmacheva Tatiana 
Published: August 2017

Abstract
The New Siberian Islands are affected by a number of Mesozoic tectonic events. The oldest event (D1a) is characterized by NW-directed thrusting within the South Anyui Suture Zone combined with north–south-trending sinistral strike-slip in the foreland during the Early Cretaceous. This compressional deformation was followed by dextral transpression along north–south-trending faults, which resulted in NE–SW shortening in the Kotelny Fold Zone (D1b). The dextral deformation can be related to a north–south-trending boundary fault zone west of the New Siberian Islands, which probably represented the Laptev Sea segment of the Amerasia Basin Transform Fault in pre-Aptian–Albian times. The presence of a transform fault west of the islands may be an explanation for the long and narrow sliver of continental lithosphere of the Lomonosov Ridge and the sudden termination of the South Anyui Suture Zone against the present Laptev Sea Rift System. The intrusion of magmatic rocks 114 myr ago was followed by NW–SE-trending sinistral strike-slip faults of unknown origin (D2). In the Late Cretaceous–Paleocene, east–west extension (D3) west of the New Siberian Islands initiated the development of the Laptev Sea Rift System, which continues until today and is largely related to the development of the Eurasian Basin.
Ice-flow reorganization within the East Antarctic Ice Sheet deep interior
Authors: Beem L. H. , Cavitte M. G. P. , Blankenship D. D. , Carter S. P. , Young D. A. , Muldoon G. R. , Jackson C. S. , Siegert M. J. 
Published: August 2017

Abstract
Near the South Pole, a large subglacial lake exists beneath the East Antarctic Ice Sheet less than 10 km from where the bed temperature is inferred to be −9°C. A thermodynamic model was used to investigate the apparent contradiction of basal water existing in the vicinity of a cold bed. Model results indicate that South Pole Lake is freezing and that neither present-day geothermal flux nor ice flow is capable of producing the necessary heat to sustain basal water at this location. We hypothesize that the lake comprises relict water formed during a different configuration of ice dynamics when significant frictional heating from ice sliding was available. Additional modelling of assumed basal sliding shows frictional heating was capable of producing the necessary heat to fill South Pole Lake. Independent evidence of englacial structures measured by airborne radar revel ice-sheet flow was more dynamic in the past. Ice sliding is estimated to have ceased between 16.8 and 10.7 ka based on an ice chronology from a nearby borehole. These findings reveal major post-Last Glacial Maximum ice-dynamic change within the interior of East Antarctica, demonstrating that the present interior ice flow is different than that under full glacial conditions.
The Combination of Metformin and Valproic Acid Induces Synergistic Apoptosis in the Presence of p53 and Androgen Signaling in Prostate Cancer
Authors: Tran Linh N.K. , Kichenadasse Ganessan , Butler Lisa M. , Centenera Margaret M. , Morel Katherine L. , Ormsby Rebecca J. , Michael Michael Z. , Lower Karen M. , Sykes Pamela J. 
Published: August 2017

Abstract
We investigated the potential of combining the hypoglycemic drug metformin (MET) and the antiepileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced antitumor responses in prostate cancer. Prostate cancer cell lines (LNCaP and PC-3), normal prostate epithelial cells (PrEC), and patient-derived prostate tumor explants were treated with MET and/or VPA. Proliferation and apoptosis were assessed. The role of p53 in response to MET + VPA was assessed in cell lines using RNAi in LNCaP (p53+) and ectopic expression of p53 in PC-3 (p53−). The role of the androgen receptor (AR) was investigated using the AR antagonist enzalutamide. The combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC-3, with no significant effect in PrEC. LNCaP, but not PC-3, demonstrated synergistic intrinsic apoptosis in response to MET + VPA. Knockdown of p53 in LNCaP (p53+, AR+) reduced the synergistic apoptotic response as did inhibition of AR. Ectopic expression of p53 in PC-3 (p53−, AR−) increased apoptosis in response to MET + VPA. In patient-derived prostate tumor explants, MET + VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells. In conclusion, we demonstrate that MET + VPA can synergistically kill more prostate cancer cells than either drug alone. The response is dependent on the presence of p53 and AR signaling, which have critical roles in prostate carcinogenesis. Further in vivo/ex vivo preclinical studies are required to determine the relative efficacy of MET + VPA as a potential treatment for prostate cancer. Mol Cancer Ther; 16(12); 2689–700. ©2017 AACR.
Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example
Authors: Eke Iris , Makinde Adeola Y. , Aryankalayil Molykutty J. , Sandfort Veit , Palayoor Sanjeewani T. , Rath Barbara H. , Liotta Lance , Pierobon Mariaelena , Petricoin Emanuel F. , Brown Matthew F. , Stommel Jayne M. , Ahmed Mansoor M. , Coleman C. Norman 
Published: August 2017

Abstract
Implementing targeted drug therapy in radio-oncologic treatment regimens has greatly improved the outcome of cancer patients. However, the efficacy of molecular targeted drugs such as inhibitory antibodies or small molecule inhibitors essentially depends on target expression and activity, which both can change during the course of treatment. Radiotherapy has previously been shown to activate prosurvival pathways, which can help tumor cells to adapt and thereby survive treatment. Therefore, we aimed to identify changes in signaling induced by radiation and evaluate the potential of targeting these changes with small molecules to increase the therapeutic efficacy on cancer cell survival. Analysis of “The Cancer Genome Atlas” database disclosed a significant overexpression of AKT1, AKT2, and MTOR genes in human prostate cancer samples compared with normal prostate gland tissue. Multifractionated radiation of three-dimensional–cultured prostate cancer cell lines with a dose of 2 Gy/day as a clinically relevant schedule resulted in an increased protein phosphorylation and enhanced protein–protein interaction between AKT and mTOR, whereas gene expression of AKT, MTOR, and related kinases was not altered by radiation. Similar results were found in a xenograft model of prostate cancer. Pharmacologic inhibition of mTOR/AKT signaling after activation by multifractionated radiation was more effective than treatment prior to radiotherapy. Taken together, our findings provide a proof-of-concept that targeting signaling molecules after activation by radiotherapy may be a novel and promising treatment strategy for cancers treated with multifractionated radiation regimens such as prostate cancer to increase the sensitivity of tumor cells to molecular targeted drugs. Mol Cancer Ther; 17(2); 355–67. ©2017 AACR.
See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”
MicroRNA-720 Regulates E-cadherin–αE-catenin Complex and Promotes Renal Cell Carcinoma
Authors: Bhat Nadeem S. , Colden Melissa , Dar Altaf A. , Saini Sharanjot , Arora Prerna , Shahryari Varahram , Yamamura Soichiro , Tanaka Yuichiro , Kato Taku , Majid Shahana , Dahiya Rajvir 
Published: August 2017

Abstract
miRNAs are implicated in regulating cancer progression and metastasis. Here, we show that miR-720 is positively associated with renal cell carcinoma (RCC). Elevated levels of miR-720 were observed in a panel of RCC cell lines and clinical tissues compared with nonmalignant cell line and normal samples. Loss of miR-720 function inhibited proliferation, migration, and invasion and induced apoptosis in RCC cell lines in vitro and repressed tumor growth in xenograft mouse models. Conversely, gain of miR-720 function in nonmalignant HK-2 cells induced procancerous characteristics. Silencing of miR-720 caused a marked induction in the levels of endogenous αE-catenin and E-cadherin protein levels in anti720 transfected cells compared with control, whereas miR-720 overexpression in RCC cell lines reduced activity of a luciferase reporter gene fused to the wild-type αE-catenin or E-cadherin 3′UTR compared with nonspecific 3′UTR control, indicating that αE-catenin–E-cadherin complex is a direct and functional target of miR-720 in RCC. We also observed attenuation of β-catenin, CD44, and Akt expression in RCC cells transfected with miR-720 inhibitor compared with control. Furthermore, miR-720 exhibited clinical significance in RCC. Expression of miR-720 significantly distinguished malignant from normal samples. Elevated miR-720 levels positively correlated with higher Fuhrman grade, pathologic stage, and poor overall survival of RCC patients. These findings uncover a new regulatory network in RCC involving metastasis-promoting miR-720 that directly targets expression of key metastasis-suppressing proteins E-cadherin and αE-catenin complex. These results suggest that therapeutic regulation of miR-720 may provide an opportunity to regulate EMT and metastasis in RCC. Mol Cancer Ther; 16(12); 2840–8. ©2017 AACR.
Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer
Authors: Haricharan Svasti , Punturi Nindo , Singh Purba , Holloway Kimberly R. , Anurag Meenakshi , Schmelz Jacob , Schmidt Cheryl , Lei Jonathan T. , Suman Vera , Hunt Kelly , Olson John A. , Hoog Jeremy , Li Shunqiang , Huang Shixia , Edwards Dean P. , Kavuri Shyam M. , Bainbridge Matthew N. , Ma Cynthia X. , Ellis Matthew J. 
Published: August 2017

Abstract
Significant endocrine therapy–resistant tumor proliferation is present in ≥20% of estrogen receptor–positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor–resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care.
Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy–resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168–83. ©2017 AACR.
This article is highlighted in the In This Issue feature, p. 1047
Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models
Authors: Mata Melinda , Gerken Claudia , Nguyen Phuong , Krenciute Giedre , Spencer David M. , Gottschalk Stephen 
Published: August 2017

Abstract
Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CAR) has had limited success for solid tumors in early-phase clinical studies. We reasoned that introducing into CAR T cells an inducible costimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)–binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T cells expressing HER2–CARζ and a MyD88/CD40–based iCO molecule (HER2ζ.iCO T cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2ζ.iCO T cells without CID and T cells expressing HER2–CAR.CD28ζ. HER2ζ.iCO T cells with CID also significantly improved survival in vivo in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2ζ.iCO T cells in vivo. Thus, expressing MyD88/CD40–based iCO molecules in CAR T cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors.
Significance: Inducible activation of MyD88 and CD40 in CAR T cells with a small-molecule drug not only enhances their effector function, resulting in potent antitumor activity in preclinical solid tumors, but also enables their remote control post infusion. Cancer Discov; 7(11); 1306–19. ©2017 AACR.
This article is highlighted in the In This Issue feature, p. 1201
Comparison of Acute Thrombogenicity for Metallic and Polymeric Bioabsorbable Scaffolds
Authors: Waksman Ron , Lipinski Michael J. , Acampado Eduardo , Cheng Qi , Adams Lila , Torii Sho , Gai Jiaxiang , Torguson Rebecca , Hellinga David M. , Westman Peter C. , Joner Michael , Zumstein Philine , Kolodgie Frank D. , Virmani Renu 
Published: August 2017

Background—
A comparison in acute thrombogenicity between the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold and the Absorb bioresorbable vascular scaffold has not been performed. This study assessed acute thrombogenicity of Magmaris compared with Absorb and the Orsiro hybrid drug-eluting stent in a porcine arteriovenous shunt model.

Methods and Results—

An ex vivo porcine carotid jugular arteriovenous shunt was established and connected to SYLGARD tubing containing the Magmaris, Absorb, and Orsiro scaffolds/stents and allowed to run in the shunt for a maximum of 1 hour. Twelve shunts (2 shunt runs per pig) were run comparing the 3 scaffolds in alternating order. Nested generalized linear mixed models were used to compare variables between scaffold groups while adjusting for variability between shunt runs. Confocal fluorescent microscopy costaining CD61/CD42b demonstrated that both Magmaris (3.0%) and Orsiro (4.6%) had less platelet coverage of the total scaffold compared with Absorb (21.8%). Scanning electron microscopy demonstrated significantly less thrombus deposition to Magmaris as a percentage of the total scaffold compared with Absorb (5.0% versus 16.1%,
P
=0.02). Magmaris had significantly less PM-1–positive neutrophil and CD14-positive monocyte adherence compared with both Orsiro and Absorb. Orsiro had significantly less monocyte deposition compared with Absorb.

Conclusions—
Despite a similar scaffold strut thickness, the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold was significantly less thrombogenic compared with the Absorb bioresorbable vascular scaffold in an ex vivo porcine arteriovenous shunt model. Further studies are needed to determine whether the reduced thrombogenicity of Magmaris will result in reductions in major cardiovascular events.
Cangrelor in Older Patients Undergoing Percutaneous Coronary Intervention
Authors: Cavender Matthew A. , Bhatt Deepak L. , Stone Gregg W. , Steg Ph. Gabriel , Gibson C. Michael , Hamm Christian W. , Price Matthew J. , Prats Jayne , Elkin Steven , Deliargyris Efthymios N. , Mahaffey Kenneth W. , White Harvey D. , Harrington Robert A. 
Published: August 2017

Background—
Older patients treated with percutaneous coronary intervention are at increased risk of periprocedural events.

Methods and Results—

CHAMPION (cangrelor versus standard therapy to achieve optimal management of platelet inhibition) PHOENIX randomized 11 145 patients to cangrelor or clopidogrel. We sought to determine the outcomes in the prespecified subgroup of patients ≥75 years old (n=2010; 18%). Cangrelor resulted in directionally consistent effects on the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) in patients ≥75 years old (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.50–1.02) and in those <75 years old (OR, 0.81; 95% CI, 0.67–0.98;
P
[interaction]=0.55). Age ≥75 years was an independent predictor of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate/severe bleeding (1.0% versus 0.3%; adjusted OR, 2.94; 95% CI, 1.28–6.77;
P
=0.01) when compared with patients <75 years old. There was no significant difference in GUSTO moderate/severe bleeding with cangrelor versus clopidogrel (1.1% versus 1.0%; OR, 1.07; 95% CI 0.45–2.53) in patients ≥75 years old or in those <75 years old (0.4% versus 0.2%; OR, 2.24; 95% CI, 1.02–4.93;
P
[interaction]=0.21). For the net composite end point of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis plus GUSTO moderate/severe bleeding, the OR for cangrelor in those ≥75 years old was 0.75 (6.4% versus 8.3%; 95% CI, 0.54–1.05;
P
=0.09). The effects were similar in those <75 years old (4.9% versus 5.8%; OR, 0.85; 95% CI, 0.70–1.02;
P
=0.08;
P
[interaction]=0.53).

Conclusions—
Patients ≥75 years old have an overall ≈3-fold increased odds of moderate/severe bleeding. Cangrelor, when compared with clopidogrel, provides similar efficacy and in patients ≥75 years old as in those <75 years old but does not increase the risk of major bleeding.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01156571.
Type 2 Diabetes Mellitus and Impaired Renal Function Are Associated With Brain Alterations and Poststroke Cognitive Decline
Authors: Ben Assayag Einor , Eldor Roy , Korczyn Amos D. , Kliper Efrat , Shenhar-Tsarfaty Shani , Tene Oren , Molad Jeremy , Shapira Itzhak , Berliner Shlomo , Volfson Viki , Shopin Ludmila , Strauss Yehuda , Hallevi Hen , Bornstein Natan M. , Auriel Eitan 
Published: August 2017

Background and Purpose—
Type 2 diabetes mellitus (T2DM) is associated with diseases of the brain, kidney, and vasculature. However, the relationship between T2DM, chronic kidney disease, brain alterations, and cognitive function after stroke is unknown. We aimed to evaluate the inter-relationship between T2DM, impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort.

Methods—
The TABASCO (Tel Aviv brain acute stroke cohort) is a prospective cohort of stroke/transient ischemic attack survivors. The volume and white matter integrity, ischemic lesions, and brain and hippocampal volumes were measured at baseline using 3-T MRI. Cognitive tests were performed on 507 patients, who were diagnosed as having mild cognitive impairment, dementia, or being cognitively intact after 24 months.

Results—
At baseline, T2DM and impaired renal function (estimated creatinine clearance [eCCl] <60 mL/min) were associated with smaller brain and hippocampal volumes, reduced cortical thickness, and worse white matter microstructural integrity. Two years later, both T2DM and eCCl <60 mL/min were associated with poorer cognitive scores, and 19.7% of the participants developed cognitive decline (mild cognitive impairment or dementia). Multiple analysis, controlling for age, sex, education, and apolipoprotein E4, showed a significant association of both T2DM and eCCl <60 mL/min with cognitive decline. Having both conditions doubled the risk compared with patients with T2DM or eCCl <60 mL/min alone and almost quadrupled the risk compared with patients without either abnormality.

Conclusions—
T2DM and impaired renal function are independently associated with abnormal brain structure, as well as poorer performance in cognitive tests, 2 years after stroke. The presence of both conditions quadruples the risk for cognitive decline. T2DM and lower eCCl have an independent and additive effect on brain atrophy and the risk of cognitive decline.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01926691.
Freedom of Religion or Belief and Employment Law
Authors: Vickers Lucy 
Published: August 2017

Abstract
This article explores the extent to which the jurisprudence of the European Convention on Human Rights has promoted the protection of freedom of religion or belief in the context of the workplace since the decision in Kokkinakis v. Greece. As a preliminary question, it explores whether and why freedom of religion or belief extends to the employment relationship. It then considers two main areas where freedom of religion or belief interacts with employment: the rights of religious workers to manifest religion or belief at work, and the rights of religious organisations to impose religious requirements on their staff.
Corporate governance in Colombian universities
Authors: Flórez-Parra Jesús Mauricio , López-Pérez María Victoria , López-Hernández Antonio Manuel 
Published: August 2017

In a context of greater demands in terms of accountability and transparency in management, we analyse the extent to which Corporate Governance (CG) mechanisms have been adopted and we define the model of governance in universities in Colombia. In the field of higher education, there are usually no compulsory requirements related to CG. Nevertheless, governance mechanisms are nowadays crucial in determining the objectives, strategies and direction of universities. Based on a survey of 81 rectors of higher education institutions in Colombia, we analyse the models of CG adopted (managerial and stakeholder models). The results contribute to a better understanding of key CG concepts at universities. Points for practitioners There is an increasing awareness of the importance of improving the mechanisms of governance that may help to achieve greater effectiveness and efficiency in the management of resources and awareness of society. The analysis of the predominant CG models, the stakeholder model and the managerial model, and the way in which Colombian universities are introducing these models could be used to promote the establishment of a common legal framework. This model should be flexible and include different opinions and preferences. The results may be useful and could be transferred to other countries that have the same characteristics.