Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome

Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood. Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes. Results: Hierarchical clustering of human breast cancers defined four distinct miRNA clusters (G1-G4) associated with distinguishable relapse-free survival by Kaplan-Meier analysis. The cyclin D1-regulated miRNA signature included several oncomirs, was conserved in multiple breast cancer cell lines, was associated with the G2 tumor miRNA cluster, ERα+ status, better outcome and activation of the Wnt pathway. The coding and non-coding genome were discordant within breast cancer subtypes. Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK. Cyclin D1 restrained DKK1 via the 3\u27UTR. In vivo studies using inducible transgenics confirmed cyclin D1 induces Wnt-dependent gene expression. Conclusion: The non-coding genome defines breast cancer subtypes that are discordant with their coding genome subtype suggesting distinct evolutionary drivers within the tumors. Cyclin D1 orchestrates expression of a miRNA signature that induces Wnt/β-catenin signaling, therefore cyclin D1 serves both upstream and downstream of Wnt/β-catenin signaling

An NLP Analysis of Health Advice Giving in the Medical Research Literature

Health advice – clinical and policy recommendations – plays a vital role in guiding medical practices and public health policies. Whether or not authors should give health advice in medical research publications is a controversial issue. The proponents of actionable research advocate for the more efficient and effective transmission of science evidence into practice. The opponents are concerned about the quality of health advice in individual research papers, especially that in observational studies. Arguments both for and against giving advice in individual studies indicate a strong need for identifying and accessing health advice, for either practical use or quality evaluation purposes. However, current information services do not support the direct retrieval of health advice. Compared to other natural language processing (NLP) applications, health advice has not been computationally modeled as a language construct either. A new information service for directly accessing health advice should be able to reduce information barriers and to provide external assessment in science communication. This dissertation work built an annotated corpus of scientific claims that distinguishes health advice according to its occurrence and strength. The study developed NLP-based prediction models to identify health advice in the PubMed literature. Using the annotated corpus and prediction models, the study answered research questions regarding the practice of advice giving in medical research literature. To test and demonstrate the potential use of the prediction model, it was used to retrieve health advice regarding the use of hydroxychloroquine (HCQ) as a treatment for COVID-19 from LitCovid, a large COVID-19 research literature database curated by the National Institutes of Health. An evaluation of sentences extracted from both abstracts and discussions showed that BERT-based pre-trained language models performed well at detecting health advice. The health advice prediction model may be combined with existing health information service systems to provide more convenient navigation of a large volume of health literature. Findings from the study also show researchers are careful not to give advice solely in abstracts. They also tend to give weaker and non-specific advice in abstracts than in discussions. In addition, the study found that health advice has appeared consistently in the abstracts of observational studies over the past 25 years. In the sample, 41.2% of the studies offered health advice in their conclusions, which is lower than earlier estimations based on analyses of much smaller samples processed manually. In the abstracts of observational studies, journals with a lower impact are more likely to give health advice than those with a higher impact, suggesting the significance of the role of journals as gatekeepers of science communication. For the communities of natural language processing, information science, and public health, this work advances knowledge of the automated recognition of health advice in scientific literature. The corpus and code developed for the study have been made publicly available to facilitate future efforts in health advice retrieval and analysis. Furthermore, this study discusses the ways in which researchers give health advice in medical research articles, knowledge of which could be an essential step towards curbing potential exaggeration in the current global science communication. It also contributes to ongoing discussions of the integrity of scientific output. This study calls for caution in advice-giving in medical research literature, especially in abstracts alone. It also calls for open access to medical research publications, so that health researchers and practitioners can fully review the advice in scientific outputs and its implications. More evaluative strategies that can increase the overall quality of health advice in research articles are needed by journal editors and reviewers, given their gatekeeping role in science communication

Value and efficacy of transcranial direct current stimulation in the rehabilitation of neurocognitive disorders: A critical review since 2000.

open3siNon-invasive brain stimulation techniques, including transcranial direct current stimulation (t-DCS) have been used in the rehabilitation of cognitive function in a spectrum of neurological disorders. The present review outlines methodological communalities and differences of t-DCS procedures in neurocognitive rehabilitation. We consider the efficacy of tDCS for the management of specific cognitive deficits in four main neurological disorders by providing a critical analysis of recent studies that have used t-DCS to improve cognition in patients with Parkinson’s Disease, Alzheimer’s Disease, Hemi-spatial Neglect and Aphasia. The evidence from this innovative approach to cognitive rehabilitation suggests that tDCS can influence cognition. However, the results show a high variability between studies both on the methodological approach adopted and the cognitive functions aspects. The review also focuses both on methodological issues such as technical aspects of the stimulation ( electrodes position and dimension; current intensity; duration of protocol) and on the inclusion of appropriate assessment tools for cognition. A further aspect considered is the best timing to administer tDCS: before, during after cognitive rehabilitation. We conclude that more studies with shared methodology are needed to have a better understanding of the efficacy of tDCS as a new tool for rehabilitation of cognitive disorders in a range of neurological disordersopenCappon, D; Jahanshahi, M; Bisiacchi, PCappon, Davide; Jahanshahi, M; Bisiacchi, Patrizi

Variability in non-invasive brain stimulation studies: reasons and results

Non-invasive brain stimulation techniques (NIBS), such as Theta Burst Stimulation (TBS), Paired Associative Stimulation (PAS) and transcranial Direct Current Stimulation (tDCS), are widely used to probe plasticity in the human motor cortex (M1). Although TBS, PAS and tDCS differ in terms of physiological mechanisms responsible for experimentally-induced cortical plasticity, they all share the ability to elicit long-term potentiation (LTP) and depression (LTD) in M1. However, NIBS techniques are all affected by relevant variability in intra- and inter-subject responses. A growing number of factors contributing to NIBS variability have been recently identified and reported. In this review, we have readdressed the issue of variability in human NIBS studies. We have first briefly discussed the physiological mechanisms responsible for TBS, PAS and tDCS-induced cortical plasticity. Then, we have provided statistical measures of intra- and inter-subject variability, as calculated in previous studies. Finally, we have reported in detail known sources of variability by categorizing them into physiological, technical and statistical factors. Improving knowledge about sources of variability could lead to relevant advances in designing new tailored NIBS protocols in physiological and pathological conditions