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Background Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA and/or DNA damage-response inhibitor (DDRi) therapies. Methods We used a multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies and mechanistic studies to assess SLFN11 as a potential biomarker for stratification of patients treated with several DDA and/or DDRi in the preclinical and clinical setting. Results SLFN11 protein associated with both preclinical and patient treatment response to DDA, but not to non-DDA or DDRi therapies, such as WEE1 inhibitor or olaparib in breast cancer. SLFN11-low/absent cancers were identified across different tumour types tested. Combinations of DDA with DDRi targeting the replication-stress response (ATR, CHK1 and WEE1) could re-sensitise SLFN11-absent/low cancer models to the DDA treatment and were effective in upper gastrointestinal and genitourinary malignancies. Conclusion SLFN11 informs on the standard of care chemotherapy based on DDA and the effect of selected combinations with ATR, WEE1 or CHK1 inhibitor in a wide range of cancer types and models.

INTRODUCTION Myoelectric hands progressed from single grip hands (traditional myoelectric devices (TH)) to be multi-grip hands (MGH) which are hypothesized to bring more degrees of freedom, greater range of motion and improved grasping capabilities1,2. Their impact on patients’ lives has been documented in only a few case studies. The Strategic Consortium for Upper Limb Prosthetic Technologies (SCULPT) aims to assess the potential benefits MGH with respect to function and patient satisfaction compared to TH systems. Abstract PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32049/24463 How to cite: Popovic I, Cutti A, Ryan T, Schaefer M, Andres E, Wuestefeld D, Winkler C, Baun K, Bischof B, Braatz F, Miguelez J, Conyers D, Hahn A. DO MULTI-GRIP HANDS INCREASE FUNCTION AND PATIENT SATISFACTION WHEN COMPARED TO TRADITIONAL MYOELECTRIC HANDS? CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, POSTER PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32049 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

Background— A hallmark of heart failure is impaired cytoplasmic Ca 2+ handling of cardiomyocytes. It remains unknown whether specific alterations in nuclear Ca 2+ handling via altered excitation-transcription coupling contribute to the development and progression of heart failure. Methods and Results— Using tissue and isolated cardiomyocytes from nonfailing and failing human hearts, as well as mouse and rabbit models of hypertrophy and heart failure, we provide compelling evidence for structural and functional changes of the nuclear envelope and nuclear Ca 2+ handling in cardiomyocytes as remodeling progresses. Increased nuclear size and less frequent intrusions of the nuclear envelope into the nuclear lumen indicated altered nuclear structure that could have functional consequences. In the (peri)nuclear compartment, there was also reduced expression of Ca 2+ pumps and ryanodine receptors, increased expression of inositol-1,4,5-trisphosphate receptors, and differential orientation among these Ca 2+ transporters. These changes were associated with altered nucleoplasmic Ca 2+ handling in cardiomyocytes from hypertrophied and failing hearts, reflected as increased diastolic Ca 2+ levels with diminished and prolonged nuclear Ca 2+ transients and slowed intranuclear Ca 2+ diffusion. Altered nucleoplasmic Ca 2+ levels were translated to higher activation of nuclear Ca 2+ /calmodulin-dependent protein kinase II and nuclear export of histone deacetylases. Importantly, the nuclear Ca 2+ alterations occurred early during hypertrophy and preceded the cytoplasmic Ca 2+ changes that are typical of heart failure. Conclusions— During cardiac remodeling, early changes of cardiomyocyte nuclei cause altered nuclear Ca 2+ signaling implicated in hypertrophic gene program activation. Normalization of nuclear Ca 2+ regulation may therefore be a novel therapeutic approach to prevent adverse cardiac remodeling.

PURPOSE: The aim of this study was to investigate prospectively whether MRI plaque imaging can identify patients with asymptomatic carotid artery stenosis who have an increased risk for future cerebral events. MRI plaque imaging allows categorization of carotid stenosis into different lesion types (I-VIII). Within these lesion types, lesion types IV-V and VI are regarded as rupture-prone plaques, whereas the other lesion types represent stable ones. METHODS: Eighty-three consecutive patients (45 male (54.2%); age 54-88 years (mean 73.2 years)) presenting with an asymptomatic carotid stenosis of 50-99% according to ECST-criteria were recruited. Patients were imaged with a 1.5-T scanner. T1-, T2-, time-of-flight-, and proton-density weighted studies were performed. The carotid plaques were classified as lesion type I-VIII. Clinical endpoints were ischemic stroke, TIA or amaurosis fugax. Survival analysis and log rank test were used to ascertain statistical significance. RESULTS: Six out of 83 patients (7.2%) were excluded: 4 patients had insufficient MR image quality; 1 patient was lost-to-follow-up; 1 patient died shortly after the baseline MRI plaque imaging. The following results were obtained by analyzing the remaining 77 patients. The mean time of follow-up was 41.1 months. During follow-up, n = 9 (11.7%) ipsilateral ischemic cerebrovascular events occurred. Only patients presenting with the high-risk lesion types IV-V and VI developed an ipsilateral cerebrovascular event versus none of the patients presenting with the stable lesion types III, VII, and VIII (n = 9 (11.7%) vs. n = 0 (0%) during follow-up). Event-free survival was higher among patients with the MRI-defined stable lesion types (III, VII, and VIII) than in patients with the high-risk lesion types (IV-V and VI) (log rank test P

Background Plaque imaging based on magnetic resonance imaging (MRI) represents a new modality for risk assessment in atherosclerosis. It allows classification of carotid plaques in high-risk and low-risk lesion types (I-VIII). Type 2 diabetes mellitus (DM 2) represents a known risk factor for atherosclerosis, but its specific influence on plaque vulnerability is not fully understood. This study investigates whether MRI-plaque imaging can reveal differences in carotid plaque features of diabetic patients compared to nondiabetics. Methods 191 patients with moderate to high-grade carotid artery stenosis were enrolled after written informed consent was obtained. Each patient underwent MRI-plaque imaging using a 1.5-T scanner with phased-array carotid coils. The carotid plaques were classified as lesion types I-VIII according to the MRI-modified AHA criteria. For 36 patients histology data was available. Results Eleven patients were excluded because of insufficient MR-image quality. DM 2 was diagnosed in 51 patients (28.3%). Concordance between histology and MRI-classification was 91.7% (33/36) and showed a Cohen's kappa value of 0.81 with a 95% CI of 0.98-1.15. MRI-defined high-risk lesion types were overrepresented in diabetic patients (n = 29; 56.8%). Multiple logistic regression analysis revealed association between DM 2 and MRI-defined high-risk lesion types (OR 2.59; 95% CI [1.15-5.81]), independent of the degree of stenosis. Conclusion DM 2 seems to represent a predictor for the development of vulnerable carotid plaques irrespective of the degree of stenosis and other risk factors. MRI-plaque imaging represents a new tool for risk stratification of diabetic patients. See Commentary: http://www.biomedcentral.com/1741-7015/8/78/abstract