bluuebunny/crossref_metadata_2025_split huggingface dataset:
PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer
Authors: Lok Benjamin H. , Gardner Eric E. , Schneeberger Valentina E. , Ni Andy , Desmeules Patrice , Rekhtman Natasha , de Stanchina Elisa , Teicher Beverly A. , Riaz Nadeem , Powell Simon N. , Poirier John T. , Rudin Charles M. 
Published: July 2016

Abstract
Purpose: PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy.
Experimental Design: Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, was analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6.0 arrays. In vitro talazoparib efficacy was measured by cell viability assays. For functional studies, CRISPR/Cas9 and shRNA were used for genomic editing and transcript knockdown, respectively. Protein levels were assessed by immunoblotting and immunohistochemistry (IHC). Quantitative synergy of talazoparib and temozolomide was determined in vitro. In vivo efficacy of talazoparib, temozolomide, and the combination was assessed in patient-derived xenograft (PDX) models.
Results: We identified SLFN11, but not HRD genomic scars, as a consistent correlate of response to all three PARPi assessed, with loss of SLFN11 conferring resistance to PARPi. We confirmed these findings in vivo across multiple PDX and defined IHC staining for SLFN11 as a predictor of talazoparib response. As temozolomide has activity in SCLC, we investigated combination therapy with talazoparib and found marked synergy in vitro and efficacy in vivo, which did not solely depend on SLFN11 or MGMT status.
Conclusions: SLFN11 is a relevant predictive biomarker of sensitivity to PARP inhibitor monotherapy in SCLC and we identify combinatorial therapy with TMZ as a particularly promising therapeutic strategy that warrants further clinical investigation. Clin Cancer Res; 23(2); 523–35. ©2016 AACR.
LMWH in the prevention of preeclampsia and fetal growth restriction in women without thrombophilia
Authors: Mastrolia Salvatore , Novack Lena , Thachil Jecko , Rabinovich Anat , Pikovsky Oleg , Klaitman Vered , Loverro Giuseppe , Erez Offer 
Published: July 2016

SummaryPlacental mediated pregnancy complications such as preeclampsia and fetal growth restriction (FGR) are common, serious, and associated with increased morbidity and mortality. We conducted a systematic review and meta-analysis to determine the effect of treatment with low-molecular-weight heparins (LMWHs) for secondary prevention of these complications in non thrombophilic women. We searched the electronic databases PubMed, Scopus, and Cochrane Library for randomised controlled trials addressing this question. Five studies including 403 patients met the inclusion criteria, 68 developed preeclampsia and 118 FGR. The studies were very heterogeneous in terms of inclusion criteria, LMWH preparation, and dosage. Meta-analyses were performed using random-effect models. The overall use of LMWHs was associated with a risk reduction for preeclampsia (Relative risk (RR) 0.366; 95 % confidence interval (CI), 0.219–0.614) and FGR (RR 0.409; 95 % CI, 0.195–0.932) vs. no treatment. From the data available for analysis it appears that the use of Dalteparin is associated with a risk reduction for preeclampsia (p=0.002) and FGR (p<0.001); while Enoxaparin is associated with risk reduction for preeclampsia (p=0.013) but not for FGR (p=0.3). In spite of the small number of studies addressing the research question, and the high variability among them, our meta-analysis found a modest beneficial effect of LMWH for secondary prevention of preeclampsia and FGR. Further studies are needed to address these questions before a definite conclusion can be reached.Supplementary Material to this article is available online at www.thrombosis-online.com.
Adjusting enoxaparin dosage according to anti-FXa levels and pregnancy outcome in thrombophilic women
Authors: Nachum Zohar , Gavish Israel , Romano Shabtai , Braverman Meirav , Garmi Gali , Salim Raed 
Published: July 2016

SummaryWomen with thrombophilias and previous placenta-mediated pregnancy complications (PMPC) have an increased risk of both recurrent PMPC and venous thromboembolism (VTE) during subsequent pregnancies. We aimed to examine whether enoxaparin dose adjusted according to anti-factor Xa levels compared to a fixed dose would reduce the risk of PMPC in subsequent pregnancies. In a randomised trial, conducted at a single teaching hospital, pregnant women with thrombophilia and previous PMPC were enrolled in a 1:1 ratio to either a fixed dose of 40 mg daily enoxaparin or adjusted dose according to anti-factor Xa plasma levels. The primary outcome was a composite that included any of the following: pregnancy loss after enrollment, pre-eclampsia, birthweight <10th percentile, placental abruption, or VTE. Overall, 144 women were needed to detect a decrease of 20 % in the incidence of the composite outcome among the adjusted dose group. Between 2009 and 2015, 144 women consented; four in the fixed-dose group were excluded. Overall, 66 and 74 in the fixed- and adjusted-dose groups, respectively, were included. Demographic and obstetric characteristics were comparable. Composite outcome occurred in 12 (18.2 %) and 20 (27.0 %) women in the fixed- and adjusted-dose groups, respectively (p=0.24). Gestational age at delivery, preterm births, and birthweights were similar between the two groups. In conclusion, dose of enoxaparin adjusted according to anti-factor Xa levels compared to fixed dose, does not reduce the risk of PMPC recurrence in thrombophilic women.ClinicalTrial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01068795.
Patient-independent variables affecting the assessment of aspirin responsiveness by serum thromboxane measurement
Authors: Petrucci Giovanna , Rizzi Alessandro , Cavalca Viviana , Habib Aida , Pitocco Dario , Veglia Fabrizio , Ranalli Paola , Zaccardi Francesco , Pagliaccia Francesca , Tremoli Elena , Patrono Carlo , Rocca Bianca 
Published: July 2016

SummaryThe serum TXB2 (sTXB2) assay reflects the pharmacodynamics of platelet inhibition by low-dose aspirin. However, different studies reported variable sTXB2 values. sTXB2 assay requires whole blood incubation at 37 °C as a condition for optimal thrombin generation, arachidonic acid release and its metabolism by platelet cyclooxygenase-1 to form TXA2. Access to 37 °C incubation may be variably delayed, and different methods to quantitate sTXB2 may contribute to variable results between different Centers. We investigated whether delaying 37 °C incubation and/or analytical issues affect sTXB2 concentrations, biasing the assessment of aspirin responsiveness. Sixty-eight samples from 54 volunteers, on- and off-aspirin, were incubated at 37 °C immediately after sampling (reference sample) or after 5, 10, 15, 20, 30 or 60 minutes at room temperature (RT); 8 samples remained at RT 60 minutes, without subsequent incubation; 314 sera were measured by enzyme immunoassay (EIA) and liquid chromatography-tandem mass-spectrometry (LC/MS-MS) methods. sTXB2 concentrations decreased exponentially as a function of the delay before 37 °C incubation, ranging from 94 ± 11 % at 5 minutes to 23 ± 22 % of the reference sample after 60 minutes at RT. There was high agreement between EIA and LC/MS-MS. Moreover, we simulated the influence of a 15– or 30-minute delayed incubation on 300 sTXB2 measurements from previously-studied, aspirin-treated patients. Delayed incubation reduced the percentage of aspirin ‘non-responders’ by 22 % to 52 %, depending on the response threshold. In conclusion, a variable delay in the 37 °C incubation of blood samples may affect the assessment of platelet cyclooxygenase-1 inhibition by aspirin and confound the characterization of the determinants of aspirin responsiveness.
High-Resolution Mapping of Postinfarction Reentrant Ventricular Tachycardia
Authors: Anter Elad , Tschabrunn Cory M. , Buxton Alfred E. , Josephson Mark E. 
Published: July 2016

Background:
In vivo description of ventricular tachycardia (VT) circuits is limited by insufficient spatiotemporal resolution. We used a novel high-resolution mapping technology to characterize the electrophysiological properties of the postinfarction reentrant VT circuit.

Methods:
In 15 swine, myocardial infarction was induced by left anterior descending artery balloon occlusion. Animals were studied 6 to 8 weeks after myocardial infarction. Activation mapping of VTs was performed by using the Rhythmia mapping system. Activation time was based on a combination of bipolar and unipolar electrograms. The response to overdrive pacing from different zones of the circuit was examined.

Results:
A total of 56 monomorphic VTs were induced (3.8±2.1 per animal). Among these, 21 (37.5%) were hemodynamically stable and allowed mapping of the circuit. Isthmuses were 16.4±7.2 mm long and 7.4±2.8 mm wide. Conduction velocities were slowest at the inward curvature into the isthmus entrance (0.28±0.2 m/s), slightly faster at the outward curvature exit (0.40±0.3 m/s) and nearly normal at the central isthmus (0.62±0.2 m/s). In 3 animals, 2 VT morphologies with opposite axes sharing the same isthmus were mapped. Conduction velocities within the shared isthmus were dependent on the activation vector, consistently slower at the proximal curvature. Overdrive pacing from isthmus sites determined by activation mapping was consistent with entrainment criteria for isthmus. However, dimensions of the isthmus defined by entrainment exceeded dimensions of the isthmus measured by activation mapping by 32±18%.

Conclusions:
In postinfarction reentrant VT, conduction velocities are slowest at the proximal and distal curvatures. Entrainment mapping overestimates the true size of the isthmus. High-resolution activation mapping of VT may better guide ablation therapy.
Cruise Observation of Rossby Waves with Finite Wavelengths Propagating from the Pacific to the South China Sea
Authors: Xie Lingling , Zheng Quanan , Tian Jiwei , Zhang Shuwen , Feng Ying , Yi Xiaofei 
Published: July 2016

AbstractThis study deals with the physical properties and 3D structures of the wave motions with finite wavelengths of O(100–550) km in the tropical western North Pacific and their variation as propagating from the Pacific to the South China Sea (SCS) using conductivity–temperature–depth observations taken in October and November 2005 and concurrent satellite altimeter data. Three wave components with wavelength bands of O(100), O(200), and O(550) km are derived from the isopycnal undulation signals along 21°, 18°, and 15°N using the ensemble empirical mode decomposition analysis. Their maximum amplitudes are over 100 m in the layer of 1000–2000 m. Phase speeds are derived from cruise-observed vertical profiles of zonal-mean geostrophic flow velocity and the Brunt–Väisälä frequency based on linear quasigeostrophic wave theory with background flow and topography. The speeds are also derived from concurrent sea level anomaly data with the objective Radon transform method. They are close to that of the first baroclinic mode of theoretical solutions, implying that the observed wave motions possess the physical properties of Rossby waves (RWs). The vertical structures of the first generalized modes are derived from cruise observations at three sections. It is shown that the RWs continuously propagate from the Pacific to the SCS, and the available potential energy of RWs 1 and 2 intensify 3–4 times in the Luzon Strait and the SCS compared to that in the Pacific.
Injectable Aorta Tissue Paste for Vocal Fold Medialization
Authors: Burns James A. , Botelho Jaime L. , Bell Jonathan I. , Faquin William , Lopez-Guerra Gerardo , Ackerman Jerome L. , Kobler James B. 
Published: July 2016

Objectives: Aortic homografts integrate well with laryngeal tissue when used in reconstructive surgery. It was hypothesized that a paste of aortic homograft, rich in slow-to-degrade elastin, would compare favorably in residence time and biocompatibility to predicate materials used for vocal fold injection-medialization. Methods: An injectable aorta paste (AP) was made by pulverizing aortic homografts at −196°C (cryomilling). To assess residence time and biocompatibility, 0.3 cc was injected subdermally in guinea pigs (n = 3 per 2-, 4-, 8-, 16-, 24-week time points) followed by histological analysis. To test particle size versus residence time, APs made using 80 or 200 seconds of cryomilling were compared. Implant characteristics of AP were then compared to Restylane, Radiesse Voice (Hydroxylapatite), Radiesse Voice Gel, and Cymetra in additional animals (n = 6 per 4-, 8-, 12-week time points). Results: Injected AP formed ovoid masses with minimal inflammation. Cellular infiltration was mild and increased with survival time. There was a gradual reduction of implant volume to ~40% at 24 weeks. Increased residence time for paste with larger particles (80 cryomilling seconds) was noted. Von Kossa staining showed progressive calcification of the AP. Cymetra was difficult to reconstitute reliably but formed subdermal masses similar to AP in shape, size, and reactivity and without calcification. The other predicates showed good biocompatibility but spread more widely and erratically in the tissue. Conclusion: Aortic paste is easy to create, biocompatible, degrades slowly, and forms well-defined implants in guinea pig subdermal tissue. The AP implants calcified over time, and experiments are ongoing to determine the source of calcification and how it might be controlled or exploited clinically.
A retrospective analysis of the effect of blood transfusion on cerebral oximetry entropy and acute kidney injury
Authors: Engoren Milo , Brown Russell R. , Dubovoy Anna 
Published: July 2016

Purpose: Acute anemia is associated with both cerebral dysfunction and acute kidney injury and is often treated with red blood cell transfusion. We sought to determine if blood transfusion changed the cerebral oximetry entropy, a measure of the complexity or irregularity of the oximetry values, and if this change was associated with subsequent acute kidney injury. Methods: This was a retrospective, case-control study of patients undergoing cardiac surgery with cardiopulmonary bypass at a tertiary care hospital, comparing those who received a red blood cell transfusion to those who did not. Acute kidney injury was defined as a perioperative increase in serum creatinine by ⩾26.4 μmol/L or by ⩾50% increase. Entropy was measured using approximate entropy, sample entropy, forbidden word entropy and basescale4 entropy in 500-point sets. Results: Forty-four transfused patients were matched to 88 randomly selected non-transfused patients. All measures of entropy had small changes in the transfused group, but increased in the non-transfused group (p<0.05, for all comparisons). Thirty-five of 132 patients (27%) suffered acute kidney injury. Based on preoperative factors, patients who suffered kidney injury were similar to those who did not, including baseline cerebral oximetry levels. After analysis with hierarchical logistic regression, the change in basescale4 entropy (odds ratio = 1.609, 95% confidence interval = 1.057–2.450, p = 0.027) and the interaction between basescale entropy and transfusion were significantly associated with subsequent development of acute kidney injury. Conclusions: The transfusion of red blood cells was associated with a smaller rise in entropy values compared to non-transfused patients, suggesting a change in the regulation of cerebral oxygenation, and these changes in cerebral oxygenation are also associated with acute kidney injury.
Hemorheological abnormalities and their associations with coronary blood flow in patients with cardiac syndrome X: a comparison between males and females
Authors: Yi Jeong-Eun , Youn Ho-Joong 
Published: July 2016

Aim: The role of elevated whole blood viscosity (WBV) in the pathogenesis of atherosclerosis is well known. We sought to investigate the gender differences in the association between WBV, coronary blood flow and tissue oxygen delivery index (TODI) in cardiac syndrome X (CSX). Methods: Forty-six CSX patients and 14 healthy volunteers were enrolled. The coronary flow parameters were obtained with transthoracic Doppler echocardiography and WBV was measured (at high-shear and low-shear rates of 300s-1 and 5s-1, respectively) using a scanning capillary tube viscometer. TODI was determined from the ratio of hematocrit to WBV measured at a low-shear rate of 5s-1. Results: In male patients, the mean diastolic coronary flow velocity (CFV) and diastolic velocity time integral (VTI) were significantly decreased compared to control group (all p<0.05) and the WBV showed significant negative correlation with peak systolic CFV (r = −0.559 at 300s-1, r = −0.438 at 5s-1), mean systolic CFV (r = −0.577 at 300s-1, r = −0.488 at 5s-1), systolic VTI (r = −0.576 at 300s-1, r = −0.530 at 5s-1) and diastolic VTI (r = −0.553 at 300s-1, r = −0.551 at 5s-1) (all p<0.01). Meanwhile, although female patients showed no significant relationships between WBV and coronary flow parameters, TODI were significantly decreased compared to the control group (3.64 ± 0.34 vs. 4.07 ± 0.38%/centipoises (cP), respectively, p=0.008). Conclusion: Our study suggests that there are gender-related differences in the pathogenesis of microvascular angina and gender-specific approaches for CSX patients might be needed.
ACL Fibers Near the Lateral Intercondylar Ridge Are the Most Load Bearing During Stability Examinations and Isometric Through Passive Flexion
Authors: Nawabi Danyal H. , Tucker Scott , Schafer Kevin A. , Zuiderbaan Hendrik Aernout , Nguyen Joseph T. , Wickiewicz Thomas L. , Imhauser Carl W. , Pearle Andrew D. 
Published: July 2016

Background: The femoral insertion of the anterior cruciate ligament (ACL) has direct and indirect fiber types located within the respective high (anterior) and low (posterior) regions of the femoral footprint. Hypothesis: The fibers in the high region of the ACL footprint carry more force and are more isometric than the fibers in the low region of the ACL footprint. Study Design: Controlled laboratory study. Methods: Ten fresh-frozen cadaveric knees were mounted to a robotic manipulator. A 134-N anterior force at 30° and 90° of flexion and combined valgus (8 N·m) and internal (4 N·m) rotation torques at 15° of flexion were applied simulating tests of anterior and rotatory stability. The ACL was sectioned at the femoral footprint by detaching either the higher band of fibers neighboring the lateral intercondylar ridge in the region of the direct insertion or the posterior, crescent-shaped fibers in the region of the indirect insertion, followed by the remainder of the ACL. The kinematics of the ACL-intact knee was replayed, and the reduction in force due to each sectioned portion of insertion fibers was measured. Isometry was assessed at anteromedial, center, and posterolateral locations within the high and low regions of the femoral footprint. Results: With an anterior tibial force at 30° of flexion, the high fibers carried 83.9% of the total anterior ACL load compared with 16.1% in the low fibers ( P < .001). The high fibers also carried more anterior force than the low fibers at 90° of flexion (95.2% vs 4.8%; P < .001). Under combined torques at 15° of flexion, the high fibers carried 84.2% of the anterior ACL force compared with 15.8% in the low fibers ( P < .001). Virtual ACL fibers placed at the anteromedial portion of the high region of the femoral footprint were the most isometric, with a maximum length change of 3.9 ± 1.5 mm. Conclusion: ACL fibers located high within the femoral footprint bear more force during stability testing and are more isometric during flexion than low fibers. Clinical Relevance: It may be advantageous to create a “higher” femoral tunnel during ACL reconstruction at the lateral intercondylar ridge.
Enhanced osteogenesis on biofunctionalized poly(ɛ-caprolactone)/poly(m-anthranilic acid) nanofibers
Authors: Guler Zeliha , Silva Jorge C , Sarac Abdulkadir S 
Published: July 2016

Biofunctionalized nanofibers with a desired biological function can be used as a tissue engineering scaffold due to their small fiber diameters and porous structure. In the present study, poly(ɛ-caprolactone)/poly( m-anthranilic acid) nanofibers were biofunctionalized with covalent immobilization of bone morphogenetic protein-2 (BMP-2) through 1-ethyl-3-(dimethyl-aminopropyl) carbodiimide hydrochloride/ N-hydroxysuccinimide activation. Fourier transform infrared analysis of the nanofiber surfaces confirmed the successful immobilization. The amount of immobilized BMP-2 was determined with bicinchoninic acid protein assay. The nanofibers before and after BMP-2 immobilization were non-cytotoxic and enhanced the attachment and proliferation of Saos-2 cells. Biofunctionalization of nanofibers with BMP-2 promoted in vitro osteogenic activity. The alkaline phosphatase activity and calcium mineralizatio of cells after 14 days of in vitro culture were enhanced on nanofibers with immobilized BMP-2.
Multistate transitional models for measuring adherence to breast cancer screening: A population-based longitudinal cohort study with over two million women
Authors: Sutradhar R , Gu S , Paszat LF 
Published: July 2016

Objective Prior work on the disparities among women in breast cancer screening adherence has been methodologically limited. This longitudinal study determines and examines the factors associated with becoming adherent. Methods In a cohort of Canadian women aged 50–74, a three-state transitional model was used to examine adherence to screening for breast cancer. The proportion of time spent being non-adherent with screening was calculated for each woman during her observation window. Using age as the time scale, a relative rate multivariable regression was implemented under the three-state transitional model, to examine the association between covariates (all time-varying) and the rate of becoming adherent. Results The cohort consisted of 2,537,960 women with a median follow-up of 8.46 years. Nearly 31% of women were continually up-to-date with breast screening. Once a woman was non-adherent, the rate of becoming adherent was higher among longer term residents (relative rate = 1.289, 95% confidence interval 1.275–1.302), those from wealthier neighbourhoods, and those who had an identifiable primary care provider who was female or had graduated in Canada. Conclusion Individual and physician-level characteristics play an important role in a woman’s adherence to screening. This work improves the quality of evidence regarding disparities among women in adherence to breast cancer screening and provides a novel methodological foundation to investigate adherence for other types of screening, including cervix and colorectal cancer screening.