Dchs1-Fat4 regulation of osteogenic differentiation in mouse.

In human, mutations of the protocadherins FAT4 and DCHS1 result in Van Maldergem syndrome, which is characterised, in part, by craniofacial abnormalities. Here, we analyse the role of Dchs1-Fat4 signalling during osteoblast differentiation in mouse. We show that Fat4 and Dchs1 mutants mimic the craniofacial phenotype of the human syndrome and that Dchs1-Fat4 signalling is essential for osteoblast differentiation. In Dchs1/Fat4 mutants, proliferation of osteoprogenitors is increased and osteoblast differentiation is delayed. We show that loss of Dchs1-Fat4 signalling is linked to increased Yap-Tead activity and that Yap is expressed and required for proliferation in osteoprogenitors. In contrast, Taz is expressed in more-committed Runx2-expressing osteoblasts, Taz does not regulate osteoblast proliferation and Taz-Tead activity is unaffected in Dchs1/Fat4 mutants. Finally, we show that Yap and Taz differentially regulate the transcriptional activity of Runx2, and that the activity of Yap-Runx2 and Taz-Runx2 complexes is altered in Dchs1/Fat4 mutant osteoblasts. In conclusion, these data identify Dchs1-Fat4 as a signalling pathway in osteoblast differentiation, reveal its crucial role within the early Runx2 progenitors, and identify distinct requirements for Yap and Taz during osteoblast differentiation.

The mutational landscape of the adult healthy parous and nulliparous human breast.

The accumulation of somatic mutations in healthy human tissues has been extensively characterized, but the mutational landscape of the healthy breast is still poorly understood. Our analysis of whole-genome sequencing shows that in line with other healthy organs, the healthy breast during the reproduction years accumulates mutations with age, with the rate of accumulation in the epithelium of 15.24 ± 5 mutations/year. Both epithelial and stromal compartments contain mutations in breast-specific driver genes, indicative of subsequent positive selection. Parity- and age-associated differences are evident in the mammary epithelium, partly explaining the observed difference in breast cancer risk amongst women of different childbearing age. Parity is associated with an age-dependent increase in the clone size of mutated epithelial cells, suggesting that older first-time mothers have a higher probability of accumulating oncogenic events in the epithelium compared to younger mothers or nulliparous women. In conclusion, we describe the reference genome of the healthy female human breast during reproductive years and provide evidence of how parity affects the genomic landscape of the mammary gland.

Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy.

AIMS: Hippo signalling is an evolutionarily conserved pathway that controls organ size by regulating apoptosis, cell proliferation, and stem cell self-renewal. Recently, the pathway has been shown to exert powerful growth regulatory activity in cardiomyocytes. However, the functional role of this stress-related and cell death-related pathway in the human heart and cardiomyocytes is not known. In this study, we investigated the role of the transcriptional co-activators of Hippo signalling, YAP and TAZ, in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in response to cardiotoxic agents and investigated the effects of modulating the pathway on cardiomyocyte function and survival. METHODS AND RESULTS: RNA-sequencing analysis of human heart samples with doxorubicin-induced end-stage heart failure and healthy controls showed that YAP and ERBB2 (HER2) as upstream regulators of differentially expressed genes correlated with doxorubicin treatment. Thus, we tested the effects of doxorubicin on hiPSC-CMs in vitro. Using an automated high-content screen of 96 clinically relevant antineoplastic and cardiotherapeutic drugs, we showed that doxorubicin induced the highest activation of YAP/TAZ nuclear translocation in both hiPSC-CMs and control MCF7 breast cancer cells. The overexpression of YAP rescued doxorubicin-induced cell loss in hiPSC-CMs by inhibiting apoptosis and inducing proliferation. In contrast, silencing of YAP and TAZ by siRNAs resulted in elevated mitochondrial membrane potential loss in response to doxorubicin. hiPSC-CM calcium transients did not change in response to YAP/TAZ silencing. CONCLUSIONS: Our results suggest that Hippo signalling is involved in clinical anthracycline-induced cardiomyopathy. Modelling with hiPSC-CMs in vitro showed similar responses to doxorubicin as adult cardiomyocytes and revealed a potential cardioprotective effect of YAP in doxorubicin-induced cardiotoxicity.

SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells.

In many tumors, cells transition reversibly between slow-proliferating tumor-initiating cells (TIC) and their differentiated, faster-growing progeny. Yet, how transcriptional regulation of cell-cycle and self-renewal genes is orchestrated during these conversions remains unclear. In this study, we show that as breast TIC form, a decrease in cell-cycle gene expression and increase in self-renewal gene expression are coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long noncoding RNA (lncRNA) that we named Stem Cell Inhibitory RNA Transcript (SCIRT), which was markedly upregulated in tumorspheres but colocalized with and counteracted EZH2 and SOX2 during cell-cycle and self-renewal regulation to restrain tumorigenesis. SCIRT specifically interacted with EZH2 to increase EZH2 affinity to FOXM1 without binding the latter. In this manner, SCIRT induced transcription at cell-cycle gene promoters by recruiting FOXM1 through EZH2 to antagonize EZH2-mediated effects at target genes. Conversely, on stemness genes, FOXM1 was absent and SCIRT antagonized EZH2 and SOX2 activity, balancing toward repression. These data suggest that the interaction of an lncRNA with EZH2 can alter the affinity of EZH2 for its protein-binding partners to regulate cancer cell state transitions. SIGNIFICANCE: These findings show that a novel lncRNA SCIRT counteracts breast tumorigenesis by opposing transcriptional networks associated with cell cycle and self-renewal.See related commentary by Pardini and Dragomir, p. 535.

Patient Feedback on a Warfarin Action Plan Used in a Local Australian Physician Practice Setting.

BACKGROUND: Warfarin is a high-risk medicine, and older persons (those aged 65 years and older)1,2 who take this therapy need medicines information about it that is at a level which is both understandable and comprehensive to improve their knowledge about the risks and benefits of warfarin therapy.3,4 Therefore, the primary objective of this study was to report patient feedback on a Warfarin Action Plan (WAP) (leaflet) and identify patients' preferences regarding its content and format. The secondary objective was to canvass in-depth feedback regarding the participants' information needs and current information-seeking practices with respect to warfarin therapy. METHOD: In an Australian General Practice medical centre setting, a qualitative study comprising 34 individual interviews was conducted. Emergent themes were elicited via a qualitative analysis using manual inductive coding. RESULTS: The majority of participants gave very positive feedback on the WAP leaflet, stating that it was a useful and concise resource. In canvasing this feedback, 4 themes emerged: (1) the need for information about warfarin therapy, (2) reliance on doctors and/or pharmacists for information, (3) the need for information to normalize their daily life, and (4) patients and carers acting on the new information. CONCLUSION: The WAP is a simple and well-received tool that meets the knowledge and education needs about warfarin therapy for older people and their carers.

Evaluating the Understandability and Actionability of Web-Based Education Materials for Patients Taking Non-vitamin K Oral Anticoagulants.

BACKGROUND: More patients are now taking high-risk medicines such as non-vitamin K oral anticoagulants (NOACs). Hence, patient education materials need to be in an understandable format so that they can be empowered to act on their knowledge. Factors such as health literacy and the design of the medicine information material may influence the patient's ability to understand and act on key information. METHOD: The PRISMA checklist was used to inform the study design. A structured search was conducted to obtain all freely accessible online educational resources designed for patients about the non-vitamin K antagonists (NOACs) during August 2018. Three search engines were used: Google, Yahoo! and Bing, using the search terms "NOAC" and "anticoagulant" combined with "patient/consumer information and patient/consumer resources."We applied the Patient Education Materials Assessment Tool (PEMAT) to evaluate web-based patient education materials in terms of understandability and actionability for patients taking NOACs. RESULTS: Of the 35 materials included, the majority of the materials (n = 32, 91%) were rated as highly understandable (PEMAT score ≥70%), and more than three-quarters of all the materials (n = 29, 83%) were rated as poorly actionable (PEMAT score <70%). For understandability, the majority of materials neither provided a summary of the key points nor used visual aids for several items such as simple tables, illustrations, and photographs. For actionability, few materials provided a tangible tool, such as a checklist, to prompt the user into action (n = 4). Few used visual aids such as nonverbal cues to the written instructions (n = 4). CONCLUSION: To improve the understandability and actionability of most of the NOAC patient education materials, there is a need to include more summaries of information, visual aids, and tangible tools such as checklists. Further research is warranted where patients are involved in providing feedback on the design of medicine information materials for NOACs.

Patient-focused interventions to support vulnerable people using oral anticoagulants: a narrative review.

The aim of this review was to identify patient-focused interventions that have been trialed to support vulnerable patient populations taking oral anticoagulants (warfarin and the direct-acting oral anticoagulants (DOACs)) such as older persons (65 years and over), those with limited health literacy, and those from culturally and linguistically diverse (CALD) backgrounds. This review also aimed to report on the effects of these interventions on outcomes relevant to the use of anticoagulant therapy. Original articles published between 1 January 1995 and 30 June 2017 were identified using several electronic databases such as Medline, Ovid, Embase, Scopus, Cochrane, and Google Scholar. The following terms were used for the three-tiered search: Tier 1, elderly, aged, older adult, geriatrics; Tier 2, health literacy, literacy, low health literacy, low English proficiency, patient literacy; and Tier 3, ethnicity, ethnic, ethnic groups, CALD, culturally and linguistically diverse, NESB, non-English speaking background, race, racial groups, religion, religious groups, and minority groups. The terms for each tier were combined with the following terms: anticoagulants, anticoagulation, warfarin, apixaban, dabigatran, rivaroxaban, DOACS, new oral anticoagulants, novel oral anticoagulants, patient care, patient knowledge, comprehension, patient education, patient participation, and communication. A total of 41 studies were identified. Most of the interventions identified included older persons taking warfarin who were monitored using the international normalized ratio (INR) and who received patient education. Many interventions reported a significant positive impact on patients' knowledge, reduction in the number of adverse events caused by hemorrhage, and better INR control. More research on patient-focused interventions is needed that includes patients with limited health literacy, those from CALD backgrounds, and family members and caregivers of patients taking oral anticoagulants.

Patient Feedback on a Warfarin Action Plan Used in a Local Australian Physician Practice Setting.

BACKGROUND: Warfarin is a high-risk medicine, and older persons (those aged 65 years and older)1,2 who take this therapy need medicines information about it that is at a level which is both understandable and comprehensive to improve their knowledge about the risks and benefits of warfarin therapy.3,4 Therefore, the primary objective of this study was to report patient feedback on a Warfarin Action Plan (WAP) (leaflet) and identify patients' preferences regarding its content and format. The secondary objective was to canvass in-depth feedback regarding the participants' information needs and current information-seeking practices with respect to warfarin therapy. METHOD: In an Australian General Practice medical centre setting, a qualitative study comprising 34 individual interviews was conducted. Emergent themes were elicited via a qualitative analysis using manual inductive coding. RESULTS: The majority of participants gave very positive feedback on the WAP leaflet, stating that it was a useful and concise resource. In canvasing this feedback, 4 themes emerged: (1) the need for information about warfarin therapy, (2) reliance on doctors and/or pharmacists for information, (3) the need for information to normalize their daily life, and (4) patients and carers acting on the new information. CONCLUSION: The WAP is a simple and well-received tool that meets the knowledge and education needs about warfarin therapy for older people and their carers.

Health literacy and knowledge in a cohort of Australian patients taking warfarin.

OBJECTIVES: To 1) characterise older patients taking warfarin, 2) assess these patients' level of warfarin knowledge, and 3) describe their strengths and limitations in health literacy, and 4) explore relationships between participants' characteristics, warfarin knowledge and health literacy. METHODS: A warfarin knowledge questionnaire and Health Literacy Questionnaire (HLQ) were administered to older patients (aged >65 years, N=34) taking warfarin in an Australian general practice setting. RESULTS: Key gaps in participant knowledge pertained to the consequences of an international normalized ratio (INR) being below the target INR range and safety issues such as when to seek medical attention. A limitation for participants with a lower level of health literacy was the ability to appraise health information. Patients who needed assistance in completing the HLQs had significantly lower warfarin knowledge scores (p=0.03). Overseas-born participants and those taking 5 or more long-term medications had lower HLQ scores for specific scales (p<0.05). CONCLUSION: In this study warfarin knowledge gaps and a limitation of health literacy amongst a small sample of older patients were identified. The findings suggest that education and resources may need to be tailored to the needs of older patients taking warfarin and their carers to address these knowledge gaps and limitations in health literacy. Patients who may need greater support include those that need assistance in completing the HLQ, are overseas-born, or are taking 5 or more long-term medications.

Cardiac Atrophy and Heart Failure In Cancer.

Functional changes in the heart in patients with cancer can be a result of both the disease itself and various cancer therapies, and limiting cardiac damage has become an increasingly important issue as survival rates in patients with cancer have improved. Processes involved in cancer-induced cardiac atrophy may include cardiomyocyte atrophy and apoptosis, decreased protein synthesis, increased autophagy and proteolysis via the ubiquitin-proteosome system. Further to direct effects of malignancy on the heart, several chemotherapeutic agents are known to affect the myocardium, in particular the anthracyclines. The aim of this report is to review the effects of cancer and cancer treatment on the heart and what is known about the underlying mechanisms. Furthermore, clinical strategies to limit and treat cancer-associated cardiac atrophy are discussed, emphasising the benefit of a multidisciplinary approach by cardiologists and oncologists to optimise models of care to improve outcomes for patients with cancer.

Health literacy and knowledge in a cohort of Australian patients taking warfarin

Objectives: To 1) characterise older patients taking warfarin, 2) assess these patients’ level of warfarin knowledge, and 3) describe their strengths and limitations in health literacy, and 4) explore relationships between participants’ characteristics, warfarin knowledge and health literacy. Methods: A warfarin knowledge questionnaire and Health Literacy Questionnaire (HLQ) were administered to older patients (aged >65 years, N=34) taking warfarin in an Australian general practice setting. Results: Key gaps in participant knowledge pertained to the consequences of an international normalized ratio (INR) being below the target INR range and safety issues such as when to seek medical attention. A limitation for participants with a lower level of health literacy was the ability to appraise health information. Patients who needed assistance in completing the HLQshad significantly lower warfarin knowledge scores (p=0.03). Overseas-bornparticipants and those taking 5 or more long-term medications had lower HLQ scores for specific scales (p<0.05).Conclusion: In this study warfarin knowledge gaps and a limitation of health literacy amongst a small sample of older patients were identified. The findings suggest that education and resources may need to be tailored to the needs of older patients taking warfarin and their carers to address these knowledge gaps and limitations in health literacy. Patients who may need greater support include those that need assistance in completing the HLQ, are overseas-born, or are taking 5or morelong-term medications (AU)

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