Serious illness care Programme UK: assessing the 'face validity', applicability and relevance of the serious illness conversation guide for use within the UK health care setting.

BACKGROUND: When doctors have honest conversations with patients about their illness and involve them in decisions about their care, patients express greater satisfaction with care and lowered anxiety and depression. The Serious Illness Care Programme (the Programme), originally developed in the United States (U.S), promotes meaningful, realistic and focused conversations about patient's wishes, fears and worries for the future with their illness. The Serious Illness Conversation Guide (the guide) provides a framework to structure these conversations. The aim of this paper is to present findings from a study to examine the 'face validity', acceptability and relevance of the Guide for use within the United Kingdom (UK) health care setting. METHODS: A multi-stage approach was undertaken, using three separate techniques: 1. Nominal Group Technique with clinician 'expert groups' to review the Serious Illness Conversation Guide: 14 'experts' in Oncology, Palliative Care and Communication Skills; 2. Cognitive Interviews with 6 patient and public representatives, using the 'think aloud technique'; to explore the cognitive processes involved in answering the questions in the guide, including appropriateness of language, question wording and format 3. Final stakeholder review and consensus. RESULTS: Nominal Group Technique Unanimous agreement the conversation guide could provide a useful support to clinicians. Amendments are required but should be informed directly from the cognitive interviews. Training highlighted as key to underpin the use of the guide. Cognitive interviews The 'holistic' attention to the person as a whole was valued rather than a narrow focus on their disease. Some concern was raised regarding the 'formality' of some wording however and suggestions for amendments were made. Final stakeholder review Stakeholders agreed amendments to 5/13 prompts and unanimously agreed the UK guide should be implemented as a part of the pilot implementation of the Serious Illness Care Programme UK. CONCLUSION: Use of the guide has the potential to benefit patients, facilitating a 'person-centred' approach to these important conversations, and providing a framework to promote shared decision making and care planning. Further research is ongoing, to understand the impact of these conversations on patients, families and clinicians and on concordance of care delivery with expressed patient wishes.

Endothelial-to-mesenchymal transition contributes to cardiac fibrosis.

Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-beta1 (TGF-beta1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.

The type I BMP receptors, Bmpr1a and Acvr1, activate multiple signaling pathways to regulate lens formation.

BMPs play multiple roles in development and BMP signaling is essential for lens formation. However, the mechanisms by which BMP receptors function in vertebrate development are incompletely understood. To determine the downstream effectors of BMP signaling and their functions in the ectoderm that will form the lens, we deleted the genes encoding the type I BMP receptors, Bmpr1a and Acvr1, and the canonical transducers of BMP signaling, Smad4, Smad1 and Smad5. Bmpr1a and Acvr1 regulated cell survival and proliferation, respectively. Absence of both receptors interfered with the expression of proteins involved in normal lens development and prevented lens formation, demonstrating that BMPs induce lens formation by acting directly on the prospective lens ectoderm. Remarkably, the canonical Smad signaling pathway was not needed for most of these processes. Lens formation, placode cell proliferation, the expression of FoxE3, a lens-specific transcription factor, and the lens protein, alphaA-crystallin were regulated by BMP receptors in a Smad-independent manner. Placode cell survival was promoted by R-Smad signaling, but in a manner that did not involve Smad4. Of the responses tested, only maintaining a high level of Sox2 protein, a transcription factor expressed early in placode formation, required the canonical Smad pathway. A key function of Smad-independent BMP receptor signaling may be reorganization of actin cytoskeleton to drive lens invagination.

Absence of Smad3 induces neutrophil migration after cutaneous irradiation: possible contribution to subsequent radioprotection.

Our previous work showed that 6 weeks after cutaneous irradiation, mice null (knockout, KO) for Smad3, a cytoplasmic downstream mediator of transforming growth factor-beta, demonstrate less epidermal acanthosis and dermal inflammation than wild-type (WT) Smad3 mice. Analysis of the kinetics of inflammation showed that 6 to 8 hours after skin irradiation, there was a transient sevenfold increase in neutrophil influx in Smad3 KO mice compared with WT. Herein we describe bone marrow transplantation and skin grafting between WT and KO mice to assess the contribution of the neutrophil genotype compared with that of irradiated skin to the induction of neutrophil migration after irradiation. Results from bone marrow transplantation showed that WT marrow transplanted into KO mice enhanced neutrophil migration 6 to 8 hours after irradiation by 3.2-fold compared with KO marrow in WT mice. KO skin grafted onto either WT or KO animals showed a sixfold elevation of neutrophils after irradiation compared with grafted WT skin. These results suggest that the genotype of the irradiated skin, rather than the inflammatory cell, controls neutrophil influx. Circulating neutrophils, increased in WT mice after injection of granulocyte colony-stimulating factor, resulted in increased neutrophil migration to the skin 6 to 8 hours after irradiation and less skin damage 6 weeks after irradiation compared with untreated WT mice. Thus, early responses, including enhanced neutrophil influx, appear to contribute to subsequent cutaneous radioprotection.

Lateral signaling enhances TGF-beta response complexity.

TGF-beta elicits context-dependent and cell-specific effects that often appear conflicting, such as stimulation or inhibition of growth, apoptosis or differentiation. It is puzzling how such a diverse array of responses can result from binding of TGF-beta to a single receptor complex that activates a seemingly straightforward signal-transduction scheme dependent on shuttling of Smad transducer proteins from the receptor to the nucleus. Here, we discuss a novel paradigm for TGF-beta signaling in endothelial cells in which the same ligand can induce opposing effects mediated by activation of two different classes of Smads through a chimeric receptor complex.

Smad3 is key to TGF-beta-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis.

Smads2 and 3 transduce signals of TGF-beta from the cell surface to the nucleus. We used mice with a targeted deletion of Smad3 to study the specific contributions of this signaling pathway to pathogenic effects of TGF-beta. Focusing on models involving epithelial-to-mesenchymal transition (EMT), including injury to the lens and retina of the eye and to the kidney, we have found that loss of Smad3 blocks EMT and attenuates development of fibrotic sequelae. Smad3 also plays a critical role in both the tumor suppressor and pro-metastatic effects of TGF-beta in carcinogenesis. These observations suggest that development of small molecule inhibitors of Smad3 might have clinical application in treatment of fibrotic diseases as well as late stage cancers.

TGF-beta signaling: positive and negative effects on tumorigenesis.

TGF-beta binding to the cell surface triggers activation of multiple signal transduction pathways that are connected in intricate ways with each other, and with other response networks involved in sensing cellular information input. Recent data indicate that changes in signal intensity and connectivity of these pathways may underlie the complex transition of the TGF-beta pathway from tumor suppressor to oncogene during tumorigenesis.

Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.

Tubulointerstitial fibrosis is the final common result of a variety of progressive injuries leading to chronic renal failure. Transforming growth factor-beta (TGF-beta) is reportedly upregulated in response to injurious stimuli such as unilateral ureteral obstruction (UUO), causing renal fibrosis associated with epithelial-mesenchymal transition (EMT) of the renal tubules and synthesis of extracellular matrix. We now show that mice lacking Smad3 (Smad3ex8/ex8), a key signaling intermediate downstream of the TGF-beta receptors, are protected against tubulointerstitial fibrosis following UUO as evidenced by blocking of EMT and abrogation of monocyte influx and collagen accumulation. Culture of primary renal tubular epithelial cells from wild-type or Smad3-null mice confirms that the Smad3 pathway is essential for TGF-beta1-induced EMT and autoinduction of TGF-beta1. Moreover, mechanical stretch of the cultured epithelial cells, mimicking renal tubular distention due to accumulation of urine after UUO, induces EMT following Smad3-mediated upregulation of TGF-beta1. Exogenous bone marrow monocytes accelerate EMT of the cultured epithelial cells and renal tubules in the obstructed kidney after UUO dependent on Smad3 signaling. Together the data demonstrate that the Smad3 pathway is central to the pathogenesis of interstitial fibrosis and suggest that inhibitors of this pathway may have clinical application in the treatment of obstructive nephropathy.

Loss of Smad3 in acute T-cell lymphoblastic leukemia.

BACKGROUND: The receptors for transforming growth factor beta (TGF-beta) and their signaling intermediates make up an important tumor-suppressor pathway. The role of one of these intermediates--Smad3--in the pathogenesis of lymphoid neoplasia is unknown. METHODS: We measured Smad3 messenger RNA (mRNA) and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia, including 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). All nine exons of the SMAD3 gene (MADH3) were sequenced. Mice in which one or both alleles of Smad3 were inactivated were used to evaluate the role of Smad3 in the response of normal T cells to TGF-beta and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27Kip1 were deleted. RESULTS: Smad3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations were found in the MADH3 gene in T-cell ALL, and Smad3 mRNA was present in T-cell ALL and normal T cells at similar levels. In mice, the loss of one allele for Smad3 impairs the inhibitory effect of TGF-beta on the proliferation of normal T cells and works in tandem with the homozygous inactivation of p27Kip1 to promote T-cell leukemogenesis. CONCLUSIONS: Loss of Smad3 protein is a specific feature of pediatric T-cell ALL. A reduction in Smad3 expression and the loss of p27Kip1 work synergistically to promote T-cell leukemogenesis in mice.