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J. Clin. Med., Volume 2, Issue 3 (September 2013), Pages 32-175

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Research

Jump to: Review, Other

Open AccessArticle Analysis of Various Subsets of Circulating Mononuclear Cells in Asymptomatic Coronary Artery Disease
J. Clin. Med. 2013, 2(3), 32-44; doi:10.3390/jcm2030032
Received: 3 June 2013 / Revised: 11 July 2013 / Accepted: 20 July 2013 / Published: 30 July 2013
Cited by 4 | PDF Full-text (207 KB) | HTML Full-text | XML Full-text
Abstract
The objective of this study was to evaluate the correlation between multiple cardiovascular risk factors (MCRFs) and circulating mononuclear cells (CMCs) in asymptomatic coronary artery disease patients. Design and Methods: 126 subjects (54 male), aged 48 to 62 years, with asymptomatic coronary artery
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The objective of this study was to evaluate the correlation between multiple cardiovascular risk factors (MCRFs) and circulating mononuclear cells (CMCs) in asymptomatic coronary artery disease patients. Design and Methods: 126 subjects (54 male), aged 48 to 62 years, with asymptomatic coronary artery disease (CAD) documented previously with angiography, and 25 healthy volunteers were enrolled in the study. The flow cytometric technique was used for predictably distinguishing cell subsets that depend on the expression of CD14, CD34, Tie-2, CD45, and CD309 (VEGFR2). Results: The analysis of the outcome obtained shows a trend of an increase in circulating CD45CD34+ CMCs and a reduction in CMC population defined as CD14+CD309+ and CD14+CD309+Tie2+ in known asymptomatic CAD patients in comparison with healthy volunteers. Substantial correlations between CD45CD34+ and conventional cardiovascular risk factors (hs-CRP, T2DM, serum uric acid and hypertension) were found in the patient cohort. The concentrations of CD14+CD309+ and CD14+CD309+Tie2+ CMCs had effect on such factors as T2DM (RR = 1.21; 95% CI = 1.10–1.40; p = 0.008), hs-CRP > 2.54 mg/L (RR = 1.29; 95% CI = 1.12–1.58; p = 0.006), Agatston score index (RR = 1.20; 95% CI = 1.15–1.27; p = 0.034), and occurrence of three and more cardiovascular risk factors (RR = 1.31; 95% CI = 1.12–1.49; p = 0.008). Conclusion: It is postulated that the reduction in circulating CD14+CD309+ and CD14+CD309+Tei2+ CMCs is related to a number of cardiovascular risk factors in asymptomatic patients with known CAD. Full article
Open AccessArticle Short Term Culture of Human Mesenchymal Stem Cells with Commercial Osteoconductive Carriers Provides Unique Insights into Biocompatibility
J. Clin. Med. 2013, 2(3), 49-66; doi:10.3390/jcm2030049
Received: 30 May 2013 / Revised: 6 July 2013 / Accepted: 9 July 2013 / Published: 19 August 2013
Cited by 4 | PDF Full-text (917 KB) | HTML Full-text | XML Full-text
Abstract
For spinal fusions and the treatment of non-union fractures, biological substrates, scaffolds, or carriers often are applied as a graft to support regeneration of bone. The selection of an appropriate material critically influences cellular function and, ultimately, patient outcomes. Human bone marrow mesenchymal
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For spinal fusions and the treatment of non-union fractures, biological substrates, scaffolds, or carriers often are applied as a graft to support regeneration of bone. The selection of an appropriate material critically influences cellular function and, ultimately, patient outcomes. Human bone marrow mesenchymal stem cells (BMSCs) are regarded as a critical component of bone healing. However, the interactions of BMSCs and commercial bone matrices are poorly reported. BMSCs were cultured with several commercially available bone substrates (allograft, demineralized bone matrix (DBM), collagen, and various forms of calcium phosphates) for 48 h to understand their response to graft materials during surgical preparation and the first days following implantation (cell retention, gene expression, pH). At 30 and 60 min, bone chips and inorganic substrates supported significantly more cell retention than other materials, while collagen-containing materials became soluble and lost their structure. At 48 h, cells bound to β-tricalcium phosphate-hydroxyapatite (βTCP-HA) and porous hydroxyapatite (HA) granules exhibited osteogenic gene expression statistically similar to bone chips. Through 24 h, the DBM strip and βTCP-collagen became mildly acidic (pH 7.1–7.3), while the DBM poloxamer-putties demonstrated acidity (pH < 5) and the bioglass-containing carrier became basic (pH > 10). The dissolution of DBM and collagen led to a loss of cells, while excessive pH changes potentially diminish cell viability and metabolism. Extracts from DBM-poloxamers induced osteogenic gene expression at 48 h. This study highlights the role that biochemical and structural properties of biomaterials play in cellular function, potentially enhancing or diminishing the efficacy of the overall therapy. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
Open AccessArticle Aging Impairs the Proliferative Capacity of Cardiospheres, Cardiac Progenitor Cells and Cardiac Fibroblasts: Implications for Cell Therapy
J. Clin. Med. 2013, 2(3), 103-114; doi:10.3390/jcm2030103
Received: 31 July 2013 / Revised: 9 August 2013 / Accepted: 22 August 2013 / Published: 23 September 2013
Cited by 2 | PDF Full-text (1078 KB) | HTML Full-text | XML Full-text
Abstract
Introduction: Cardiospheres (CS) are self-assembling clusters of cells that can be grown from cardiac tissue. They contain a heterogeneous cell population that includes cardiac progenitor cells (CPCs) and cardiac fibroblasts. CS and CPCs have been shown to improve cardiac function after myocardial infarction
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Introduction: Cardiospheres (CS) are self-assembling clusters of cells that can be grown from cardiac tissue. They contain a heterogeneous cell population that includes cardiac progenitor cells (CPCs) and cardiac fibroblasts. CS and CPCs have been shown to improve cardiac function after myocardial infarction (MI) in experimental models and are now being studied in clinical trials. The effects of aging on the proliferative capacity of CS and CPCs, and the paracrine signaling between cell types, remain incompletely understood. Methods and Results: We compared the growth of CS from young and aging murine hearts at baseline and following MI. The number of CS from young and aging hearts was similar at baseline. However, after MI, young hearts had a dramatic increase in the number of CS that grew, but this proliferative response to MI was virtually abolished in the aging heart. Further, the proportion of cells within the CS that were CPCs (defined as Sca-1(stem cell antigen-1)+/CD45) was significantly lower in aging hearts than young hearts. Thus the number of available CPCs after culture from aging hearts was substantially lower than from young hearts. Cardiac fibroblasts from aging hearts proliferated more slowly in culture than those from young hearts. We then investigated the interaction between aging cardiac fibroblasts and CPCs. We found no significant paracrine effects on proliferation between these cell types, suggesting the impaired proliferation is a cell-autonomous problem. Conclusions: Aging hearts generate fewer CPCs, and aging CPCs have significantly reduced proliferative potential following MI. Aging cardiac fibroblasts also have reduced proliferative capacity, but these appear to be cell-autonomous problems, not caused by paracrine signaling between cell types. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
Open AccessArticle Engraftment Outcomes after HPC Co-Culture with Mesenchymal Stromal Cells and Osteoblasts
J. Clin. Med. 2013, 2(3), 115-135; doi:10.3390/jcm2030115
Received: 25 July 2013 / Revised: 22 August 2013 / Accepted: 10 September 2013 / Published: 23 September 2013
Cited by 2 | PDF Full-text (1542 KB) | HTML Full-text | XML Full-text
Abstract
Haematopoietic stem cell (HSC) transplantation is an established cell-based therapy for a number of haematological diseases. To enhance this therapy, there is considerable interest in expanding HSCs in artificial niches prior to transplantation. This study compared murine HSC expansion supported through co-culture on
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Haematopoietic stem cell (HSC) transplantation is an established cell-based therapy for a number of haematological diseases. To enhance this therapy, there is considerable interest in expanding HSCs in artificial niches prior to transplantation. This study compared murine HSC expansion supported through co-culture on monolayers of either undifferentiated mesenchymal stromal cells (MSCs) or osteoblasts. Sorted Lineage Sca-1+ c-kit+ (LSK) haematopoietic stem/progenitor cells (HPC) demonstrated proliferative capacity on both stromal monolayers with the greatest expansion of LSK shown in cultures supported by osteoblast monolayers. After transplantation, both types of bulk-expanded cultures were capable of engrafting and repopulating lethally irradiated primary and secondary murine recipients. LSKs co-cultured on MSCs showed comparable, but not superior, reconstitution ability to that of freshly isolated LSKs. Surprisingly, however, osteoblast co-cultured LSKs showed significantly poorer haematopoietic reconstitution compared to LSKs co-cultured on MSCs, likely due to a delay in short-term reconstitution. We demonstrated that stromal monolayers can be used to maintain, but not expand, functional HSCs without a need for additional haematopoietic growth factors. We also demonstrated that despite apparently superior in vitro performance, co-injection of bulk cultures of osteoblasts and LSKs in vivo was detrimental to recipient survival and should be avoided in translation to clinical practice. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)

Review

Jump to: Research, Other

Open AccessReview Bone-Targeted Agents for the Management of Breast Cancer Patients with Bone Metastases
J. Clin. Med. 2013, 2(3), 67-88; doi:10.3390/jcm2030067
Received: 24 June 2013 / Revised: 25 July 2013 / Accepted: 29 July 2013 / Published: 19 August 2013
Cited by 3 | PDF Full-text (239 KB) | HTML Full-text | XML Full-text
Abstract
Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or treatment-related
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Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or treatment-related complications. Bone metastases predispose patients to reduced survival, pain, impaired quality of life and the development of skeletal-related events. With an increased understanding of the pathophysiology of bone metastasis, effective treatments for their management have evolved and are now in widespread clinical use. This article will discuss the pathogenesis of bone metastases and review the key clinical evidence for the efficacy and safety of currently available systemic bone-targeted therapies in breast cancer patients with an emphasis on bisphosphonates and the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitors. We will also discuss novel strategies and therapies currently in development. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
Open AccessReview Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment?
J. Clin. Med. 2013, 2(3), 89-102; doi:10.3390/jcm2030089
Received: 12 June 2013 / Revised: 22 July 2013 / Accepted: 25 July 2013 / Published: 28 August 2013
PDF Full-text (567 KB) | HTML Full-text | XML Full-text
Abstract
Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in a
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Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in a vicious cycle of metastasis growth and bone destruction. The RANK-RANK ligand (RANKL) pathway plays a key role in this cycle, and inhibition of RANKL using the fully-human monoclonal antibody denosumab, has demonstrated efficacy in delaying skeletal complications associated with bone metastases in three phase 3 trials. Preclinical studies suggest that the RANKL pathway also plays a role in breast cancer tumourigenesis and migration to bone. In a subgroup analysis of the negative Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, the bisphosphonate zoledronic acid showed potential for improving survival in patients who were postmenopausal; however, a prospective study in this patient population is required to validate this observation. Ongoing trials are examining whether adjuvant blockade of the RANKL pathway using denosumab can prevent disease recurrence in patients with high-risk breast cancer. These are building on analogous studies that have shown that denosumab improves bone metastasis-free survival in prostate cancer and suggested that it confers an overall survival benefit in non-small-cell lung cancer. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
Figures

Open AccessReview Mechanisms of Metastatic Tumor Dormancy
J. Clin. Med. 2013, 2(3), 136-150; doi:10.3390/jcm2030136
Received: 26 July 2013 / Revised: 20 August 2013 / Accepted: 10 September 2013 / Published: 23 September 2013
Cited by 5 | PDF Full-text (322 KB) | HTML Full-text | XML Full-text
Abstract
Tumor metastasis can occur years after an apparent cure due to a phenomenon known as metastatic tumor dormancy; in which tumor masses or individual tumor cells are growth restricted for extended periods of time. This period of dormancy is induced and maintained by
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Tumor metastasis can occur years after an apparent cure due to a phenomenon known as metastatic tumor dormancy; in which tumor masses or individual tumor cells are growth restricted for extended periods of time. This period of dormancy is induced and maintained by several mechanisms, including: (1) Tumor microenvironment factors such as cytokine expression, immunosurveillance and angiogenesis; (2) Metastasis suppressor gene activity; and (3) Cancer therapeutics. Disseminated tumor cells (DTC) are the key cells that result in dormant tumors. However, many challenges exist towards isolating DTCs for mechanistic studies. The main DTC that may represent the dormant cell is the cancer stem cells (CSC) as they have a slow proliferation rate. In addition to limited knowledge regarding induction of tumor dormancy, there are large gaps in knowledge regarding how tumors escape from dormancy. Emerging research into cancer stem cells, immunotherapy, and metastasis suppressor genes, may lead to new approaches for targeted anti-metastatic therapy to prevent dormancy escape. Overall, an enhanced understanding of tumor dormancy is critical for better targeting and treatment of patients to prevent cancer recurrence. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
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Open AccessReview Prevention and Treatment of Bone Metastases in Breast Cancer
J. Clin. Med. 2013, 2(3), 151-175; doi:10.3390/jcm2030151
Received: 25 July 2013 / Revised: 19 August 2013 / Accepted: 22 August 2013 / Published: 24 September 2013
Cited by 3 | PDF Full-text (549 KB) | HTML Full-text | XML Full-text | Correction
Abstract
In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as
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In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression). Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach. Full article
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Other

Jump to: Research, Review

Open AccessCase Report Recurrent Fever of Unknown Origin (FUO) Due to Periodic Fever, Aphthous Stomatititis, Pharyngitis and Adenitis (FAPA) Syndrome in an Adult
J. Clin. Med. 2013, 2(3), 45-48; doi:10.3390/jcm2030045
Received: 20 July 2013 / Revised: 30 July 2013 / Accepted: 6 August 2013 / Published: 19 August 2013
Cited by 1 | PDF Full-text (143 KB) | HTML Full-text | XML Full-text
Abstract
FAPA syndrome (periodic fever, aphthous stomatititis, pharyngitis and adenitis) is a relatively new entity described in pediatric patients. In adults, reports of FAPA are limited to rare case reports. The differential diagnosis of FAPA in adults includes Behcet’s syndrome, familial Mediterranean fever (FMF),
[...] Read more.
FAPA syndrome (periodic fever, aphthous stomatititis, pharyngitis and adenitis) is a relatively new entity described in pediatric patients. In adults, reports of FAPA are limited to rare case reports. The differential diagnosis of FAPA in adults includes Behcet’s syndrome, familial Mediterranean fever (FMF), Hyper IgD syndrome and juvenile rheumatoid arthritis (JRA), i.e., adult Still’s disease. With FAPA syndrome, between episodes patients are completely asymptomatic and serologic inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and white blood cell (WBC) count are normal. The etiology of FAFA is unknown, but lack of secondary cases or clustering in close contacts, lack of seasonality, and the lack of progression for years argue against an infectious etiology. We describe an extremely rare case of an adult with a recurrent FUO with profuse night sweats and prominent chills due to FAPA syndrome. Full article

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