Germline breast cancer susceptibility genes, tumor characteristics, and survival.

BACKGROUND: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. METHODS: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. RESULTS: PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]). CONCLUSIONS: PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions

Robotic-based ACTive somatoSENSory (Act.Sens) retraining on upper limb functions with chronic stroke survivors : study protocol for a pilot randomised controlled trial

Background: Prior studies have established that senses of the limb position in space (proprioception and kinaesthesia) are important for motor control and learning. Although nearly one-half of stroke patients have impairment in the ability to sense their movements, somatosensory retraining focusing on proprioception and kinaesthesia is often overlooked. Interventions that simultaneously target motor and somatosensory components are thought to be useful for relearning somatosensory functions while increasing mobility of the affected limb. For over a decade, robotic technology has been incorporated in stroke rehabilitation for more controlled therapy intensity, duration, and frequency. This pilot randomised controlled trial introduces a compact robotic-based upper-limb reaching task that retrains proprioception and kinaesthesia concurrently.Methods: Thirty first-ever chronic stroke survivors (> 6-month post-stroke) will be randomly assigned to either a treatment or a control group. Over a 5-week period, the treatment group will receive 15 training sessions for about an hour per session. Robot-generated haptic guidance will be provided along the movement path as somatosensory cues while moving. Audio-visual feedback will appear following every successful movement as a reward. For the same duration, the control group will complete similar robotic training but without the vision occluded and robot-generated cues. Baseline, post-day 1, and post-day 30 assessments will be performed, where the last two sessions will be conducted after the last training session. Robotic-based performance indices and clinical assessments of upper limb functions after stroke will be used to acquire primary and secondary outcome measures respectively. This work will provide insights into the feasibility of such robot-assisted training clinically. Discussion: The current work presents a study protocol to retrain upper-limb somatosensory and motor functions using robot-based rehabilitation for community-dwelling stroke survivors. The training promotes active use of the affected arm while at the same time enhances somatosensory input through augmented feedback. The outcomes of this study will provide preliminary data and help inform the clinicians on the feasibility and practicality of the proposed exercise.Published versionThis study is supported by the Rehabilitation Research Institute of Singapore, Research Fellowship Program (RFP/19002)

Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection

Objective HCV infection affects millions of people worldwide, and many patients develop chronic infection leading to liver cancers. For decades, the lack of a small animal model that can recapitulate HCV infection, its immunopathogenesis and disease progression has impeded the development of an effective vaccine and therapeutics. We aim to provide a humanised mouse model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. Design Recently, we have established human liver cells with a matched human immune system in NOD-scid Il2rg−/− (NSG) mice (HIL mice). These mice are infected with HCV by intravenous injection, and the pathologies are investigated. Results In this study, we demonstrate that HIL mouse is capable of supporting HCV infection and can present some of the clinical symptoms found in HCV-infected patients including hepatitis, robust virus-specific human immune cell and cytokine responses as well as liver fibrosis and cirrhosis. Similar to results obtained from the analysis of patient samples, the human immune cells, particularly T cells and macrophages, play critical roles during the HCV-associated liver disease development in the HIL mice. Furthermore, our model is demonstrated to be able to reproduce the therapeutic effects of human interferon alpha 2a antiviral treatment. Conclusions The HIL mouse provides a model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. It could also serve as a platform for antifibrosis and immune-modulatory drug testing.Singapore. Ministry of Education (Grant MOE2012-T2-1-152)Singapore. Agency for Science, Technology and Research (Joint Council Office Development Programme 1334k00082

Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection

Objective HCV infection affects millions of people worldwide, and many patients develop chronic infection leading to liver cancers. For decades, the lack of a small animal model that can recapitulate HCV infection, its immunopathogenesis and disease progression has impeded the development of an effective vaccine and therapeutics. We aim to provide a humanised mouse model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. Design Recently, we have established human liver cells with a matched human immune system in NOD-scid Il2rg−/− (NSG) mice (HIL mice). These mice are infected with HCV by intravenous injection, and the pathologies are investigated. Results In this study, we demonstrate that HIL mouse is capable of supporting HCV infection and can present some of the clinical symptoms found in HCV-infected patients including hepatitis, robust virus-specific human immune cell and cytokine responses as well as liver fibrosis and cirrhosis. Similar to results obtained from the analysis of patient samples, the human immune cells, particularly T cells and macrophages, play critical roles during the HCV-associated liver disease development in the HIL mice. Furthermore, our model is demonstrated to be able to reproduce the therapeutic effects of human interferon alpha 2a antiviral treatment. Conclusions The HIL mouse provides a model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. It could also serve as a platform for antifibrosis and immune-modulatory drug testing.Singapore. Ministry of Education (Grant MOE2012-T2-1-152)Singapore. Agency for Science, Technology and Research (Joint Council Office Development Programme 1334k00082

A wavelet algorithm for the solution of the double layer potential equation over polygonal boundaries

In this paper we consider a piecewise linear collocation method for the solution of the double layer potential equation corresponding to Laplace's equation over polygonal domains. We give a wavelet algorithm for the computation of the corresponding stiffness matrix and for the solution of the arising matrix equation with no more than O(N x [logN]&quot;8) arithmetic operations. The error of the resulting approximate solution is of order O(N&quot;-&quot;2 x [logN]&quot;6). Finally, we give some remarks on the generalization of the algorithm to the piecewise cubic collocation and present numerical tests. (orig.)Available from TIB Hannover: RR 5549(106)+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman