Reimagining care for young adults living with type 1 diabetes.

Young adults living with type 1 diabetes often struggle to achieve what clinicians consider to be optimal levels of metabolic control. Despite the impact that this can have on a young person's future risk of complications, there are relatively few studies reporting new ways of organizing or delivering care to this cohort. In this article, we explore some of the reasons why young adult diabetes care is challenging, and describe approaches to "re-imagining" how care might be improved. The work is informed by the 'Making Care Fit' collaborative and by a program of research, entitled D1 Now, involving co-design of a complex person-centered intervention with young adults.

Improving outcomes among young adults with type 1 diabetes: the D1 Now pilot cluster randomised controlled trial.

BACKGROUND: The D1 Now intervention is designed to improve outcomes in young adults living with type 1 diabetes. It consists of three components: an agenda-setting tool, an interactive messaging system and a support worker. The aim of the D1 Now pilot cluster randomised controlled trial (RCT) was to gather and analyse acceptability and feasibility data to allow (1) further refinement of the D1 Now intervention, and (2) determination of the feasibility of evaluating the D1 Now intervention in a future definitive RCT. METHODS: A pilot cluster RCT with two intervention arms and a control arm was conducted over 12 months. Quantitative data collection was based on a core outcome set and took place at baseline and 12 months. Semi-structured interviews with participants took place at 6, 9 and 12 months. Fidelity and health economic costings were also assessed. RESULTS: Four diabetes centres and 57 young adults living with type 1 diabetes took part. 50% of eligible young adults were recruited and total loss to follow-up was 12%. Fidelity, as measured on a study delivery checklist, was good but there were three minor processes that were not delivered as intended in the protocol. Overall, the qualitative data demonstrated that the intervention was considered acceptable and feasible, though this differed across intervention components. The agenda-setting tool and support worker intervention components were acceptable to both young adults and staff, but views on the interactive messaging system were mixed. CONCLUSIONS: Some modifications are required to the D1 Now intervention components and research processes but with these in place progression to a definitive RCT is considered feasible. TRIAL REGISTRATION: ISRCTN (ref: ISRCTN74114336 ).

Piloting an Intervention to Improve Outcomes in Young Adults Living With Type 1 Diabetes: The Experience of the D1 Now Support Worker.

Introduction: D1 Now is a novel intervention which aims to support self-management and clinic engagement and improve outcomes in young adults (18-25 years) living with type 1 diabetes in Ireland. It has been developed using a systematic, theoretical, user-centred approach. The specific role of the Support Worker, one of three components of the D1 Now intervention, was developed to provide continuity and build relationships between young adults and their diabetes team. Methods: A Support Worker - an Occupational Therapist, who had a background in youth mental health - was hired as part of the D1 Now pilot randomised controlled trial and was based in one intervention site to join the existing diabetes team. Discussion: The Support Worker aimed to provide an accessible and consistent point of contact for young adults, facilitated conversations about distress, and encouraged graded goal setting and collaborative problem solving. The role afforded her with a unique window into the lived experiences of young adults with type 1 diabetes where she observed the ongoing negotiation of life and living alongside diabetes care and management. The prevalence of diabetes distress was high in the study cohort with particular challenges associated with 'all or nothing' thinking patterns as well as disordered eating behaviours. The Support Worker also played an advocacy role in supporting the diabetes team's awareness of young adults' needs and explored current barriers to care. Preliminary findings from the D1 Now pilot have identified that the role of the Support Worker was viewed positively from the perspective of young adults with type 1 diabetes.

Human bone marrow stem/stromal cell osteogenesis is regulated via mechanically activated osteocyte-derived extracellular vesicles.

Bone formation or regeneration requires the recruitment, proliferation, and osteogenic differentiation of stem/stromal progenitor cells. A potent stimulus driving this process is mechanical loading. Osteocytes are mechanosensitive cells that play fundamental roles in coordinating loading-induced bone formation via the secretion of paracrine factors. However, the exact mechanisms by which osteocytes relay mechanical signals to these progenitor cells are poorly understood. Therefore, this study aimed to demonstrate the potency of the mechanically stimulated osteocyte secretome in driving human bone marrow stem/stromal cell (hMSC) recruitment and differentiation, and characterize the secretome to identify potential factors regulating stem cell behavior and bone mechanobiology. We demonstrate that osteocytes subjected to fluid shear secrete a distinct collection of factors that significantly enhance hMSC recruitment and osteogenesis and demonstrate the key role of extracellular vesicles (EVs) in driving these effects. This demonstrates the pro-osteogenic potential of osteocyte-derived mechanically activated extracellular vesicles, which have great potential as a cell-free therapy to enhance bone regeneration and repair in diseases such as osteoporosis.

Can hi-jacking hypoxia inhibit extracellular vesicles in cancer?

Increasing evidence indicates that extracellular vesicles (EVs) are key players in undesirable cell-cell communication in cancer. However, the release of EVs is not unique to cancer cells; normal cells release EVs to perform physiological roles. Thus, selective inhibition of EV release from cancer cells is desirable. Hypoxia contributes to tumour development and aggressiveness. EV quantities and thus undesirable communications are substantially increased in hypoxia. Targeting hypoxia could selectively inhibit EV release from tumour cells without disturbing physiologically relevant EVs. The unfavourable association between hypoxia and EV release is evident in multiple tumour types; therefore, targeting hypoxia could have a broad therapeutic benefit.

Neratinib resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4.

BACKGROUND: Neratinib is in Phase 3 clinical trials but, unfortunately, the development of resistance is inevitable. Here, we investigated the effects of acquired neratinib resistance on cellular phenotype and the potential mechanism of this resistance. METHODS: Neratinib-resistant variants of HER2-positive breast cancer cells were developed and their cross-resistance investigated using cytotoxicity assays. Similarly, sensitivity of trastuzumab-resistant and lapatinib-resistant cells to neratinib was assessed. Cellular phenotype changes were evaluated using migration, invasion and anoikis assays. Immunoblotting for HER family members and drug efflux pumps, as well as enzyme activity assays were performed. RESULTS: Neratinib resistance conferred cross-resistance to trastuzumab, lapatinib and afatinib. Furthermore, the efficacy of neratinib was reduced in trastuzumab- and lapatinib-resistant cells. Neratinib-resistant cells were more aggressive than their drug-sensitive counterparts, with increased CYP3A4 activity identified as a novel mechanism of neratinib resistance. CONCLUSIONS: The potential of increased CYP3A4 activity as a biomarker and/or target to add value to neratinib warrants investigation.

Decline in ethical concerns about reproductive technologies among a representative sample of US women.

Public awareness and utilization of assisted reproductive technology has been increasing, but little is known about changes in ethical concerns over time. The National Survey of Fertility Barriers, a national, probability-based sample of US women, asked 2031 women the same set of questions about ethical concerns regarding six reproductive technologies on two separate occasions approximately 3 years apart. At Wave 1 (2004-2007), women had more concerns about treatments entailing the involvement of a third party than about treatments that did not. Ethical concerns declined between Wave 1 and Wave 2, but they declined faster for treatments entailing the involvement of a third party. Ethical concerns declined faster for women with greater levels of concern at Wave 1. Initial ethical concerns were higher, and there was less of a decline in ethical concerns for women with higher initial levels of religiosity.

The Role of Exosomes in Breast Cancer.

BACKGROUND: Although it has been long realized that eukaryotic cells release complex vesicular structures into their environment, only in recent years has it been established that these entities are not merely junk or debris, but that they are tailor-made specialized minimaps of their cell of origin and of both physiological and pathological relevance. These exosomes and microvesicles (ectosomes), collectively termed extracellular vesicles (EVs), are often defined and subgrouped first and foremost according to size and proposed origin (exosomes approximately 30-120 nm, endosomal origin; microvesicles 120-1000 nm, from the cell membrane). There is growing interest in elucidating the relevance and roles of EVs in cancer. CONTENT: Much of the pioneering work on EVs in cancer has focused on breast cancer, possibly because breast cancer is a leading cause of cancer-related deaths worldwide. This review provides an in-depth summary of such studies, supporting key roles for exosomes and other EVs in breast cancer cell invasion and metastasis, stem cell stimulation, apoptosis, immune system modulation, and anti-cancer drug resistance. Exosomes as diagnostic, prognostic, and/or predictive biomarkers and their potential use in the development of therapeutics are discussed. SUMMARY: Although not fully elucidated, the involvement of exosomes in breast cancer development, progression, and resistance is becoming increasingly apparent from preclinical and clinical studies, with mounting interest in the potential exploitation of these vesicles for breast cancer biomarkers, as drug delivery systems, and in the development of future novel breast cancer therapies.

miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity.

Exosomes (EVs) have relevance in cell-to-cell communication carrying pro-tumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down-regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)8 cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin-induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti-Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer.

Elongin C is a mediator of Notch4 activity in human renal tubule cells.

Notch proteins (Notch 1-4) are a family of trans-membrane cell surface receptors that are converted into transcriptional regulators when activated by interactions with cell surface ligands on adjacent cells. Ligand-binding stimulates proteolytic cleavage of the trans-membrane domain, releasing an active intracellular domain (ICD) that translocates to the nucleus and impacts transcription. In transit, the ICD may interact with regulatory proteins that modulate the expression and transcriptional activity. We have found that Notch4(ICD) expression is enhanced in the tubule cells of fibrotic kidneys from diabetic mice and humans and identified Notch4(ICD) interacting proteins that could be pertinent to normal and pathological functions. Using proteomic techniques, several components of the Elongin C complex were identified as candidate Notch4(ICD) interactors. Elongin C complexes can function as ubiquitin ligases capable of regulating proteasomal degradation of specific protein substrates. Our studies indicate that ectopic Elongin C expression stimulates Notch4(ICD) degradation and inhibits its transcriptional activity in human kidney tubule HK11 cells. Blocking Elongin C mediated degradation by MG132 indicates the potential for ubiquitin-mediated Elongin C regulation of Notch4(ICD). Functional interaction of Notch4(ICD) and Elongin C provides novel insight into regulation of Notch signaling in epithelial cell biology and disease.

Barriers to breast cancer screening in a managed care population.

PURPOSE: In 2006, Sharp Health Plan (SHP) conducted a campaign to increase mammography screening for at-risk female members that consisted of mailing each eligible member an informational mammography postcard with an appointment tracker. Then came an automated phone call reminder. After the mammography campaign, 70 percent of SHP members sought mammography screening while 30 percent remained nonadherent. SHP decided to conduct a survey to better understand members' barriers to breast cancer screening. DESIGN: A survey based on Prochaska and Velicier's Transtheoretical Model of Change was designed to assess members' behavioral stage and barriers to breast cancer screening. METHODOLOGY: The survey was administered to all nonadherent members via personal phone calls with nearly 50 percent of the nonadherent completing the interview. All quantitative data were examined, and a code book was created to assess additional qualitative data. Findings were further analyzed by stage of change, ethnicity/race, and region of San Diego. PRINCIPAL FINDINGS: The top three barriers identified were: Mammogram not a priority, Knowledge deficit, and Had a bad experience in the past. CONCLUSION: A common set of mammography barriers was found in the SHP member population. However, when segmented into ethnic, racial, geographic, and behavioral stage groups, various barriers were identified. SHP providers can use this information to develop more tailored interventions and to increase the rate of breast cancer screening for their member population.