Bone Marrow Osteoblast Damage by Chemotherapeutic Agents

Hematopoietic reconstitution, following bone marrow or stem cell transplantation, requires a microenvironment niche capable of supporting both immature progenitors and stem cells with the capacity to differentiate and expand. Osteoblasts comprise one important component of this niche. We determined that treatment of human primary osteoblasts (HOB) with melphalan or VP-16 resulted in increased phospho-Smad2, consistent with increased TGF-β1 activity. This increase was coincident with reduced HOB capacity to support immature B lineage cell chemotaxis and adherence. The supportive deficit was not limited to committed progenitor cells, as human embryonic stem cells (hESC) or human CD34+ bone marrow cells co-cultured with HOB pre-exposed to melphalan, VP-16 or rTGF-β1 had profiles distinct from the same populations co-cultured with untreated HOB. Functional support deficits were downstream of changes in HOB gene expression profiles following chemotherapy exposure. Melphalan and VP-16 induced damage of HOB suggests vulnerability of this critical niche to therapeutic agents frequently utilized in pre-transplant regimens and suggests that dose escalated chemotherapy may contribute to post-transplantation hematopoietic deficits by damaging structural components of this supportive niche

Comparison of active treatments for impaired glucose regulation : a Salford Royal Foundation Trust and Hitachi collaboration (CATFISH): study protocol for a randomized controlled trial

BACKGROUND: Diabetes is highly prevalent and contributes to significant morbidity and mortality worldwide. Behaviour change interventions that target health and lifestyle factors associated with the onset of diabetes can delay progression to diabetes, but many approaches rely on intensive one-to-one contact by specialists. Health coaching is an approach based on motivational interviewing that can potentially deliver behaviour change interventions by non-specialists at a larger scale. This trial protocol describes a randomized controlled trial (CATFISH) that tests whether a web-enhanced telephone health coaching intervention (IGR3) is more acceptable and efficient than a telephone-only health coaching intervention (IGR2) for people with prediabetes (impaired glucose regulation). METHODS: CATFISH is a two-parallel group, single-centre individually randomized controlled trial. Eligible participants are patients aged ≥18 years with impaired glucose regulation (HbA1c concentration between 42 and 47 mmol/mol), have access to a telephone and home internet and have been referred to an existing telephone health coaching service at Salford Royal NHS Foundation Trust, Salford, UK. Participants who give written informed consent will be randomized remotely (via a clinical trials unit) to either the existing pathway (IGR2) or the new web-enhanced pathway (IGR3) for 9 months. The primary outcome measure is patient acceptability at 9 months, determined using the Client Satisfaction Questionnaire. Secondary outcome measures at 9 months are: cost of delivery of IGR2 and IGR3, mental health, quality of life, patient activation, self-management, weight (kg), HbA1c concentration, and body mass index. All outcome measures will be analyzed on an intention-to-treat basis. A qualitative process evaluation will explore the experiences of participants and providers with a focus on understanding usability of interventions, mechanisms of behaviour change, and impact of context on delivery and user acceptability. Qualitative data will be analyzed using Framework. DISCUSSION: The CATFISH trial will provide a pragmatic assessment of whether a web-based information technology platform can enhance acceptability of a telephone health coaching intervention for people with prediabetes. The data will prove critical in understanding the role of web applications to improve engagement with evidence-based approaches to preventing diabetes. TRIAL REGISTRATION: ISRCTN16534814 . Registered on 7 February 2016

Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone.

Neoplasms have a striking tendency to metastasize or "home" to bone. Hematopoietic cells also home to bone during embryonic development, where evidence points to the chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12; expressed by osteoblasts and endothelial cells) and its receptor (CXCR4) as key elements in these processes. We hypothesized that metastatic prostate carcinomas also use the SDF-1/CXCR4 pathway to localize to the bone. To test this, levels of CXCR4 expression were determined for several human prostate cancer cell lines by reverse transcription-PCR and Western blotting. Positive results were obtained for cell lines derived from malignancies that had spread to bone and marrow. Prostate cancer cells were also observed migrating across bone marrow endothelial cell monolayers in response to SDF-1. In in vitro adhesion assays, pretreatment of the prostate cancer cells with SDF-1 significantly increased their adhesion to osteosarcomas and endothelial cell lines in a dose-dependent manner. Invasion of the cancer cell lines through basement membranes was also supported by SDF-1 and inhibited by antibody to CXCR4. Collectively, these results suggest that prostate cancers and perhaps other neoplasms may use the SDF-1/CXCR4 pathway to spread to bone

Expression of vascular endothelial growth factor in human periodontal tissues: Comparison of healthy and diabetic patients

WOS: 000187314200006PubMed ID: 12666706Background: Vascular endothelial growth factor (VEGF) induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability, but information about its role in periodontal lesions is limited. The aim of this study is to determine the association between VEGF expression in healthy and periodontally diseased tissues of healthy and diabetic patients. Methods: Ten systemically healthy and 10 Type 2 diabetic patients (DM) all diagnosed with periodontitis were enrolled into the study. Gingival samples were collected from both periodontal and healthy sites in all patients. Each patient served as his/her own control. Additionally, 10 people without any systemic or periodontal diseases were enrolled as a negative control group. Results: In the negative control group tissue samples, no VEGF expression was observed. Among the 10 systemically healthy people, no evidence of VEGF was observed in healthy gingival samples, but was found in diseased tissues in 2 cases. In the diabetic patients, VEGF was observed in 4 healthy gingival tissues and in 6 periodontal sites. VEGF was intensely present in monocytes and macrophages. Conclusion: The results of this study show that VEGF is increased in gingival tissues of diabetic patients, especially those with periodontal disease