bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers
Authors: van der Lee Miranda M.C. , Groothuis Patrick G. , Ubink Ruud , van der Vleuten Monique A.J. , van Achterberg Tanja A. , Loosveld Eline M. , Damming Désirée , Jacobs Daniëlle C.H. , Rouwette Myrthe , Egging David F. , van den Dobbelsteen Diels , Beusker Patrick H. , Goedings Peter , Verheijden Gijs F.M. , Lemmens Jacques M. , Timmers Marco , Dokter Wim H.A. 
Published: January 2015

Abstract
SYD985 is a HER2-targeting antibody–drug conjugate (ADC) based on trastuzumab and vc-seco-DUBA, a cleavable linker-duocarmycin payload. To evaluate the therapeutic potential of this new ADC, mechanistic in vitro studies and in vivo patient-derived xenograft (PDX) studies were conducted to compare SYD985 head-to-head with T-DM1 (Kadcyla), another trastuzumab-based ADC. SYD985 and T-DM1 had similar binding affinities to HER2 and showed similar internalization. In vitro cytotoxicity assays showed similar potencies and efficacies in HER2 3+ cell lines, but in cell lines with low HER2 expression, SYD985 was 3- to 50-fold more potent than T-DM1. In contrast with T-DM1, SYD985 efficiently induced bystander killing in vitro in HER2-negative (HER2 0) cells mixed with HER2 3+, 2+, or 1+ cell lines. At pH conditions relevant for tumors, cathepsin-B cleavage studies showed efficient release of the active toxin by SYD985 but not by T-DM1. These in vitro data suggest that SYD985 might be a more potent ADC in HER2-expressing tumors in vivo, especially in low HER2-expressing and/or in heterogeneous tumors. In line with this, in vivo antitumor studies in breast cancer PDX models showed that SYD985 is very active in HER2 3+, 2+, and 1+ models, whereas T-DM1 only showed significant antitumor activity in HER2 3+ breast cancer PDX models. These properties of SYD985 may enable expansion of the target population to patients who have low HER2-expressing breast cancer, a patient population with still unmet high medical need. Mol Cancer Ther; 14(3); 692–703. ©2015 AACR.
Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3–BAIAP2L1
Authors: Nakanishi Yoshito , Akiyama Nukinori , Tsukaguchi Toshiyuki , Fujii Toshihiko , Satoh Yasuko , Ishii Nobuya , Aoki Masahiro 
Published: January 2015

Abstract
Recent cancer genome profiling studies have identified many novel genetic alterations, including rearrangements of genes encoding FGFR family members. However, most fusion genes are not functionally characterized, and their potentials in targeted therapy are unclear. We investigated a recently discovered gene fusion between FGFR3 and BAI1-associated protein 2-like 1 (BAIAP2L1). We identified 4 patients with bladder cancer and 2 patients with lung cancer harboring the FGFR3–BAIAP2L1 fusion through PCR and FISH assay screens. To investigate the oncogenic potential of the fusion gene, we established an FGFR3–BAIAP2L1 transfectant with Rat-2 fibroblast cells (Rat-2_F3-B). The FGFR3–BAIAP2L1 fusion had transforming activity in Rat2 cells, and Rat-2_F3-B cells were highly tumorigenic in mice. Rat-2_F3-B cells showed in vitro and in vivo sensitivity in the selective FGFR inhibitor CH5183284/Debio 1347, indicating that FGFR3 kinase activity is critical for tumorigenesis. Gene signature analysis revealed that FGFR3–BAIAP2L1 activates growth signals, such as the MAPK pathway, and inhibits tumor-suppressive signals, such as the p53, RB1, and CDKN2A pathways. We also established Rat-2_F3-B-ΔBAR cells expressing an FGFR3–BAIAP2L1 variant lacking the Bin–Amphiphysin–Rvs (BAR) dimerization domain of BAIAP2L1, which exhibited decreased tumorigenic activity, FGFR3 phosphorylation, and F3-B-ΔBAR dimerization, compared with Rat-2_F3-B cells. Collectively, these data suggest that constitutive dimerization through the BAR domain promotes constitutive FGFR3 kinase activation and is essential for its potent oncogenic activity. Mol Cancer Ther; 14(3); 704–12. ©2015 AACR.
Regulation of monocyte/macrophage polarisation by extracellular RNA
Authors: Cabrera-Fuentes Hector , Lopez Mercedes , McCurdy Sara , Fischer Silvia , Meiler Svenja , Baumer Yvonne , Galuska Sebastian , Preissner Klaus , Boisvert William 
Published: January 2015

SummaryMonocytes/macrophages respond to external stimuli with rapid changes in the expression of numerous inflammation-related genes to undergo polarisation towards the M1 (pro-inflammatory) or M2 (antiinflammatory) phenotype. We have previously shown that, independently of Toll-like receptor activation, extracellular RNA (eRNA) could exert prothrombotic and pro-inflammatory properties in the cardiovascular system to provoke cytokine mobilisation. Here, mouse bone marrow-derived-macrophages (BMDM) differentiated with mouse macrophage-colony-stimulating factor (M-CSF) were found to be skewed towards the M1 phenotype when exposed to eRNA. This resulted in up-regulated expression of inflammatory markers such as Tnf-α and Il-6, together with Il-12 and iNOS, whereas anti-inflammatory genes such as chitinase-like proteins (Ym1/2) and macrophage mannose receptor-2 (Cd206) were significantly down-regulated. Human peripheral blood monocytes were treated with eRNA and analysed by micro-array analysis of the whole human genome, revealing an up-regulation of 79 genes by at least four-fold; 27 of which are related to signal transduction and 15 genes associated with inflammatory response. In accordance with the proposed actions of eRNA as a pro-inflammatory “alarm signal”, these data shed light on the role of eRNA in the context of chronic inflammatory diseases such as atherosclerosis.
Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome
Authors: Müller-Calleja Nadine , Köhler Antonia , Siebald Benjamin , Canisius Antje , Orning Carolin , Radsak Markus , Stein Pamela , Mönnikes René , Lackner Karl J. 
Published: January 2015

SummaryThe antiphospholipid syndrome (APS) is an autoimmune disease characterised by thromboembolic events and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Here we show that three cofactor independent human monoclonal aPL can induce transcription of NLRP3 and caspase-1 resulting in inflammasome activation specific for NLRP3. This depends fully on activation of endosomal NADPH-oxidase-2 (NOX2) by aPL. Activation of NOX2 and subsequent inflammasome activation by aPL are independent from TLR2 or TLR4. While endosomal superoxide production induces caspase-1 and NLRP3 transcription, it does not affect prae-IL-1β transcription. Therefore, release of IL-1β occurs only after activation of additional pathways like TLR7/8 or TLR2. All effects exerted by the monoclonal aPL can be reproduced with IgG fractions of APS patients proving that the monoclonal aPL are representative for the APS. IgG fractions of healthy controls or patients suffering from systemic lupus erythematosus have no effect. In a mouse model of the APS we can show inflammasome activation in vivo. Furthermore, mononuclear cells isolated from patients with the APS show an increased expression of caspase-1 and NLRP3 which is accompanied by a three-fold increased serum concentration of IL-1β suggesting chronic inflammasome activation in APS patients. In summary, we provide further evidence that endosomal NOX2 can be activated by cofactor independent aPL. This leads to induction of the NLRP3 inflammasome. Our data indicate that cofactor independent aPL might contribute significantly to the pathogenesis of the APS.
Abnormal Stress‐Related Measures of Arterial Stiffness in Middle‐Aged and Elderly Men and Women With Impaired Fasting Glucose at Risk for a First Episode of Symptomatic Heart Failure
Authors: Vasu Sujethra , Morgan Timothy M. , Kitzman Dalane W. , Bertoni Alain , Stacey Richard B. , Hamilton Craig , Chiles Caroline , Thohan Vinay , Hundley W. Gregory 
Published: January 2015

Background
Abnormal resting arterial stiffness is present in middle‐aged and elderly persons with abnormalities of fasting glucose (diabetes or impaired fasting glucose) and is associated with exercise intolerance. We sought to determine whether these same persons exhibited stress‐related abnormalities of arterial stiffness.

Methods and Results

We analyzed dobutamine magnetic resonance stress imaging results from 373 consecutively recruited persons aged 55 to 85 years with normal fasting glucose, impaired fasting glucose, or diabetes who were at risk for but without symptomatic heart failure. Personnel blinded to participant identifiers measured arterial stiffness (brachial pulse pressure/left ventricular stroke volume indexed to body surface area, the aortic elastance index [brachial end‐systolic pressure/left ventricular stroke volume indexed to body surface area], and thoracic aortic distensibility) at 80% of the maximum predicted heart rate response for age. Participants averaged 69±8 years of age; 79% were white, 92% were hypertensive, and 66% were women. After accounting for hypertension, sex, coronary artery disease, smoking, medications, hypercholesterolemia, and visceral fat, we observed an effect of glycemic status for stress measures of arterial stiffness in those with diabetes and impaired fasting glucose relative to those with normal fasting glucose (
P
=0.002,
P
=0.02, and
P
=0.003, respectively).

Conclusion
Middle‐ and older‐aged individuals with diabetes or impaired fasting glucose have higher stress measures of arterial stiffness than those with normal fasting glucose. These data emphasize the need for future studies with larger sample sizes to determine whether stress‐related elevations in arterial stiffness are related to exercise intolerance and future episodes of heart failure experienced by those with abnormalities of fasting glucose.

Clinical Trial Registration

URL:
http://clinicaltrials.gov/
. Unique identifier: NCT00542503.
Comparison of Heritability of Cystatin C‐ and Creatinine‐Based Estimates of Kidney Function and Their Relation to Heritability of Cardiovascular Disease
Authors: Arpegård Johannes , Viktorin Alexander , Chang Zheng , de Faire Ulf , Magnusson Patrik K. E. , Svensson Per 
Published: January 2015

Background

Decreased renal function is an established risk factor for cardiovascular disease (
CVD
). Causal mechanisms between estimates of renal function and
CVD
are intricate and investigation of the relative importance of genetic and environmental factors for the variability of these phenotypes could provide new knowledge.

Methods and Results

Cystatin C and creatinine levels in 12 313 twins were analyzed. Uni‐ and bivariate heritability for these traits and
CVD
was estimated through structured equation modelling and genome‐wide complex trait analysis (
GCTA
) in order to independently confirm additive genetic effects. Twin model‐estimated heritability of Cystatin C was 0.55 (95% confidence interval [
CI
], 0.49 to 0.60) in men, 0.63 (0.59 to 0.66) in women, and 0.60 (0.56 to 0.63) in both sexes combined. For creatinine, heritability estimates were in the same range. Heritability of
CVD
was 0.39 (0.02 to 0.67) in men and 0.20 (0.00 to 0.61) in women. The phenotypic correlation between Cystatin C and
CVD
correlation was 0.16 (0.12 to 0.20) in men and 0.17 (0.13 to 0.21) in women, whereas the genetic correlation in males was 0.41 (0.21 to 0.62) while it was non‐significant in females. Trough
GCTA
, the heritability of Cystatin C and creatinine in both sexes combined was estimated to 0.40 (
SE
0.07,
P
=8E
−9
) and 0.19 (
SE
0.07,
P
=0.003), respectively.

Conclusions

Twin model‐based heritability of Cystatin C was higher compared to previous studies. Co‐variation between Cystatin C and
CVD
in males was partly explained by additive genetic components, indicating that Cystatin C and
CVD
share genetic influences. The
GCTA
provided independent evidence for significant contribution of additive genetics to trait variance of Cystatin C.
Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis
Authors: Ilieva Irena P. , Hook Cayce J. , Farah Martha J. 
Published: January 2015

Abstract
The use of prescription stimulants to enhance healthy cognition has significant social, ethical, and public health implications. The large number of enhancement users across various ages and occupations emphasizes the importance of examining these drugs' efficacy in a nonclinical sample. The present meta-analysis was conducted to estimate the magnitude of the effects of methylphenidate and amphetamine on cognitive functions central to academic and occupational functioning, including inhibitory control, working memory, short-term episodic memory, and delayed episodic memory. In addition, we examined the evidence for publication bias. Forty-eight studies (total of 1,409 participants) were included in the analyses. We found evidence for small but significant stimulant enhancement effects on inhibitory control and short-term episodic memory. Small effects on working memory reached significance, based on one of our two analytical approaches. Effects on delayed episodic memory were medium in size. However, because the effects on long-term and working memory were qualified by evidence for publication bias, we conclude that the effect of amphetamine and methylphenidate on the examined facets of healthy cognition is probably modest overall. In some situations, a small advantage may be valuable, although it is also possible that healthy users resort to stimulants to enhance their energy and motivation more than their cognition.
An Alternative Framework to Investigating and Understanding Intraindividual Processes in Substance Abuse Recovery
Authors: Zheng Yao , Cleveland H. Harrington , Molenaar Peter C. M. , Harris Kitty S. 
Published: January 2015

Background: Sustained recovery from substance abuse is a dynamic intraindividual-level process. Objectives: We argue that research on recovery process will benefit from a theoretical approach that captures both the dynamic and the idiographic nature of substance abuse recovery. In addition to setting out why we believe that research on recovery can benefit from such an approach, we provide a demonstration of idiographic within-individual analyses of between- and within-day associations among negative affect, substance use craving, and positive social experiences. Design and Subjects: The data used were drawn from 39 abstinent young adults in 12-step recovery from substance abuse (mean age = 22.9, females = 12). Participants provided an average of 26.7 days of daily diary data by end-of-day collections. Unified first-order structural equation models were fit individually to predict daily levels of craving and negative affect from the previous day’s same two variables as well as from both the previous day’s and the same day’s positive social experiences. Results: Model estimates demonstrated substantial interindividual heterogeneity in their day-to-day associations in both direction and magnitude, highlighting the importance of applying idiographic approach to understanding recovery. Cluster analyses were subsequently applied to individual model estimates to identify homogeneous subgroups that demonstrated similar day-to-day association patterns, revealing two distinct subgroups that appeared to manage daily abstinence through different mechanisms. Conclusions: The idiographic approach presented provides the potential value of framing recovery as an idiosyncratic dynamic process and provides targets for tailored and adaptive treatment and recovery supporting intervention in future design and evaluation.
Long-term effects of continuous theta-burst stimulation in visuospatial neglect
Authors: Fu Wei , Song Weiqun , Zhang Yanming , Yang Yuanbin , Huo Su , Zhang Ran , Wang Maobin 
Published: January 2015

Objective To investigate whether the efficacy of continuous theta-burst stimulation (cTBS) for improving visuospatial neglect can be enhanced by providing more days of stimulation and more stimulation trains per day. Methods In a prospective study, right-handed patients with right hemisphere stroke and visuospatial neglect were randomized to cTBS or sham cTBS treatment for 2 weeks and were followed up for 4 weeks. The cTBS group received active cTBS over the posterior parietal cortex of the unaffected hemisphere, combined with conventional rehabilitation therapy. Changes in scores for two paper–pencil tests for visuospatial neglect (star cancellation and line bisection) were evaluated. Results In each group, 10 patients completed follow up. Compared with the sham group, star cancellation test scores in the cTBS group were improved by 37.03% at the end of treatment and by 47.21% after 4 weeks’ follow up, and the line bisection score improved by 21.37% at the end of treatment and by 35.99% after 4 weeks’ follow up. Conclusions These results suggest that the efficacy of cTBS in visuospatial neglect can be enhanced and prolonged by increasing the days of stimulation and the number of stimulation trains per day over the left posterior parietal cortex.
Are clients' performances on the Rowland Universal Dementia Assessment Scale associated with their functional performance? A preliminary investigation
Authors: Joliffe Laura , Brown Ted , Fielding Leesa 
Published: January 2015

Introduction The process of selecting the most appropriate cognitive assessments to use with clients presenting with symptoms of dementia is an important consideration. Are cognitive assessment results associated with the functional performance of clients presenting suspected cognitive decline? The purpose of this study was to investigate whether the Rowland Universal Dementia Assessment Scale was associated with the functional performance of clients with suspected dementia. Method A within-subjects quantitative research design was employed whereby a sample of 30 participants suspected of having dementia were recruited from three acute care hospital sites in the Melbourne metropolitan region. The Rowland Universal Dementia Assessment Scale was used to assess participants' cognitive abilities, while the Functional Independence Measure was the functional scale used. Linear regression analyses were completed. Results The six Rowland Universal Dementia Assessment Scale items were found to be significantly linked with the Functional Independence Measure total score (adjusted R2 = 0.298, p < 0.05), the Functional Independence Measure ‘cognition’ subscale score (adjusted R2 = 0.349, p < 0.05) and the Functional Independence Measure ‘physical’ subscale score (adjusted R2 = 0.244; p < 0.05). Conclusion The Rowland Universal Dementia Assessment Scale appears to be associated with the functional performance of clients with suspected dementia. The findings provide an insight into the link between cognition and everyday functional performance.
The lived experience of diabetes: Conceptualisation using a metaphor
Authors: Youngson Annabel , Cole Fiona , Wilby Helen , Cox Diane 
Published: January 2015

Introduction It is important for healthcare professionals to understand the reality of living with diabetes in order to better engage and enable people to self-manage. The purpose of this research was thus a preliminary exploration of the lived experience of diabetes. Method This qualitative study involved seven people with a diagnosis of type 1, type 2 or pre-diabetes. Data was collected via semi-structured interviews and analysed using a phenomenological approach including the use of metaphor. Findings were shared with participants using a felted metaphor of charting a course of health and wellbeing through a choppy sea. Findings: Themes explored within the elements of the metaphor included the boat (self-identity, control, balance, compliance and empowerment, emotions), the sea (physical and social environment, lifestyle, life events), the course (information gathering, change, self-action) and the boatyard (relationships with healthcare providers). Conclusion For those with type 1, type 2 and pre-diabetes, the elements of charting a course of health and wellbeing through a choppy sea are very much focused on the person in their own context, impacted by their environment, life stage, occupations and attitudes to diabetes self-management, all of which fall within the remit of occupational therapy.
Effect of Lateral Meniscal Root Tear on the Stability of the Anterior Cruciate Ligament–Deficient Knee
Authors: Shybut Theodore B. , Vega Charles E. , Haddad Jebran , Alexander Jerry W. , Gold Jonathon E. , Noble Philip C. , Lowe Walter R. 
Published: January 2015

Background: Meniscal root tears are an increasingly recognized subset of meniscal injury. The menisci are critical secondary stabilizers of the anterior cruciate ligament (ACL). The kinematic effect of lateral meniscus posterior root tear in the setting of ACL injury is not known. Purpose/Hypothesis: The purpose of this study was to determine the effect of tear of the lateral meniscal root on stability of the ACL-deficient knee. The hypothesis was that disruption of the lateral meniscal root will further destabilize the ACL-deficient knee during a simulated pivot shift. Study Design: Controlled laboratory study. Methods: Pivot-shift testing of 8 fresh-frozen cadaveric knees was performed after attachment of photoreflective flags and preparation of CT scans. Each knee was mounted in a custom activity simulator and dynamically loaded from 15° to 90° of flexion with all the permutations of the following: iliotibial band force (50, 75, 100, 125, 150, and 175 N), internal rotation moments (1, 2, and 3 N·m), and valgus moments (5 and 7 N·m). In addition, anterior stability tests were performed by applying a 90-N anterior force to the tibia at flexion angles of 15°, 30°, 45°, 60°, and 90°. During each test, the anterior tibial translation and rotation of the tibia were measured with a high-resolution multiple infrared camera motion analysis system for the following 3 conditions: ACL-intact (ACL-I), ACL-deficient (ACL-D), and ACL-deficient/lateral meniscal posterior root avulsion (ACL-D/LMR-A). Results: A pivot-shift phenomenon was observed in the ACL-D and ACL-D/LMR-A conditions. The mean tibial translation of the lateral tibial condyle during the pivot-shift maneuver was 2.62 ± 0.53 mm for the ACL-I knees, 6.01 ± 0.51 mm for the ACL-D knees ( P value vs intact: .0005), and 8.13 ± 0.75 mm for the ACL-D/LMR-A knees ( P value vs intact: <.0001). During the pivot-shift maneuver, translation was significantly increased in the ACL-D/LMR-A condition compared with the ACL-D condition ( P = .0146). Compared with the intact group, anterior tibial translation during the Lachman maneuver also increased at 30° and 90° of flexion in the ACL-D group ( P < .0001) and the ACL-D/LM group ( P < .0001). No statistically significant difference was found between the ACL-D and ACL-D/LMR-A groups during the Lachman maneuver at 30° and 90° ( P = .16 and .72, respectively). Conclusion: A tear of the lateral meniscal posterior root further reduces the stability of the ACL-deficient knee during rotational loading. Clinical Relevance: This study shows that lateral meniscal root injury further destabilizes the ACL-deficient knee and thus advances the concept that the lateral meniscus is a secondary stabilizer of the knee under pivot-shift loading. In the absence of stronger evidence, the study data suggest a rationale for surgical repair of lateral meniscal root tears encountered in the setting of ACL tears.