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1.  Phase II Study of Dasatinib (BMS-354825) in Patients With Metastatic Adenocarcinoma of the Pancreas 
The Oncologist  2013;18(10):1091-1092.
Background.
Src, EphA2, and platelet-derived growth factor receptors α and β are dysregulated in pancreatic ductal adenocarcinoma (PDAC). Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor β, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC.
Methods.
Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected.
Results.
Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8–6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6–3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival.
Conclusion.
Single-agent dasatinib does not have clinical activity in metastatic PDAC.
doi:10.1634/theoncologist.2013-0255
PMCID: PMC3805150  PMID: 24072218
2.  Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia 
The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of ischemic conditions such as coronary artery disease, peripheral arterial disease, and stroke has been explored in animal models and early-phase clinical trials. A substantial database documents the safety profile of MSC administration to humans in a large number of disease states. The mechanism of the therapeutic effect of MSC transplantation in ischemic disease has been postulated to be due to paracrine, immunomodulatory, and differentiation effects. This review provides an overview of the potential role of MSC-based therapy for critical limb ischemia (CLI), the comparison of MSC cellular therapy with angiogenesis gene therapy in CLI, and the proposed mechanism of action of MSC therapy. Preclinical efficacy data in animal models of hindlimb ischemia, current early-phase human trial data, and considerations for future MSC-based therapy in CLI will also be discussed.
doi:10.1186/scrt119
PMCID: PMC3580466  PMID: 22846185
3.  CD40 ligand is necessary and sufficient to support primary diffuse large B-cell lymphoma cells in culture: a tool for in vitro preclinical studies with primary B-cell malignancies 
Leukemia & lymphoma  2012;53(7):1390-1398.
Established cell lines are utilized extensively to study tumor biology and preclinical therapeutic development; however, they may not accurately recapitulate the heterogeneity of their corresponding primary disease. B-cell tumor cells are especially difficult to maintain under conventional culture conditions, limiting access to samples that faithfully represent this disease for preclinical studies. Here, we used primary canine diffuse large B-cell lymphoma to establish a culture system that reliably supports the growth of these cells. CD40 ligand, either expressed by feeder cells or provided as a soluble two-trimeric form, was sufficient to support primary lymphoma cells in vitro. The tumor cells retained their original phenotype, clonality and known karyotypic abnormalities after extended expansion in culture. Finally, we illustrate the utility of the feeder cell-free culture system for comparable assessment of cytotoxicity using dog and human B-cell malignancies. We conclude this system has broad applications for in vitro preclinical development for B-cell malignancies.
doi:10.3109/10428194.2011.654337
PMCID: PMC3727651  PMID: 22229753
Diffuse large B-cell lymphoma; CD40L; Primary cell culture; Canine model; Cytotoxicity assay
4.  Three years of Stem Cell Research & Therapy 
doi:10.1186/scrt196
PMCID: PMC3706755  PMID: 23635482
5.  Stem Cell Research & Therapy in 2012 
doi:10.1186/scrt107
PMCID: PMC3392776  PMID: 22548746
7.  Brief Report: Phase II Trial of Rebeccamycin Analogue, a Dual Topoisomerase I and II Inhibitor, in Relapsed “Sensitive” Small Cell Lung Cancer 
Journal of Thoracic Oncology  2012;7(4):751-754.
Relapsed small cell lung cancer (SCLC) carries a poor prognosis. Toposiomerase I and II inhibitors and DNA damaging agents are considered amongst the most active agents against SCLC. Rebeccamaycin analogue (RA, Becatacarin) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase I and II as well as DNA intercalating properties. We performed a phase II trial of RA in relapsed, sensitive SCLC with the primary endpoint of response rate. Patients with previously treated SCLC who relapsed more than 60 days after completion of first-line chemotherapy were treated with RA administered i.v. at a dose of 140 mg/m2 on days 1–5 of 21 day cycles for a maximum of 6 cycles. Eligibility included ECOG PS 0–2 and adequate organ function. A 2-stage design was employed. Twenty evaluable patients were enrolled. Median age was 61 years. Two (10%) patients had a partial response and six had stable disease. The clinical benefit rate (CBR) was 40% (95% CI 23–64%). The median progression free survival was 2 months (95% CI 1.2–5.2 mo). The median survival was 6.7 months (95% CI: 3.3–8.0 months). No treatment-related deaths occurred. Grade 4 neutropenia and thrombocytopenia occurred in 23% and 14% of patients respectively. In conclusion, RA has single-agent activity in relapsed, sensitive SCLC with manageable toxicities but is unlikely to provide any superiority compared to existing agents for this disease.
doi:10.1097/JTO.0b013e31824abca2
PMCID: PMC3310884  PMID: 22425925
8.  A poisonous surprise under the coat of the African crested rat 
Plant toxins are sequestered by many animals and the toxicity is frequently advertised by aposematic displays to deter potential predators. Such ‘unpalatability by appropriation’ is common in many invertebrate groups and also found in a few vertebrate groups. However, potentially lethal toxicity by acquisition has so far never been reported for a placental mammal. Here, we describe complex morphological structures and behaviours whereby the African crested rat, Lophiomys imhausi, acquires, dispenses and advertises deterrent toxin. Roots and bark of Acokanthera schimperi (Apocynaceae) trees are gnawed, masticated and slavered onto highly specialized hairs that wick up the compound, to be delivered whenever the animal is bitten or mouthed by a predator. The poison is a cardenolide, closely resembling ouabain, one of the active components in a traditional African arrow poison long celebrated for its power to kill elephants.
doi:10.1098/rspb.2011.1169
PMCID: PMC3248729  PMID: 21813554
Lophiomys; Acokanthera; ouabain; toxicity; aposematic; mammal
9.  Arginase Treatment Prevents the Recovery of Canine Lymphoma and Osteosarcoma Cells Resistant to the Toxic Effects of Prolonged Arginine Deprivation 
PLoS ONE  2013;8(1):e54464.
Rapidly growing tumor cells require a nutrient-rich environment in order to thrive, therefore, restricting access to certain key amino acids, such as arginine, often results in the death of malignant cells, which frequently display defective cell cycle check-point control. Healthy cells, by contrast, become quiescent and remain viable under arginine restriction, displaying full recovery upon return to arginine-rich conditions. The use of arginase therapy to restrict available arginine for selectively targeting malignant cells is currently under investigation in human clinical trials. However, the suitability of this approach for veterinary uses is unexplored. As a prelude to in vivo studies in canine malignancies, we examined the in vitro effects of arginine-deprivation on canine lymphoid and osteosarcoma cell lines. Two lymphoid and 2 osteosarcoma cell lines were unable to recover following 6 days of arginine deprivation, but all remaining cell lines displayed full recovery upon return to arginine-rich culture conditions. These remaining cell lines all proved susceptible to cell death following the addition of arginase to the cultures. The lymphoid lines were particularly sensitive to arginase, becoming unrecoverable after just 3 days of treatment. Two of the osteosarcoma lines were also susceptible over this time-frame; however the other 3 lines required 6–8 days of arginase treatment to prevent recovery. In contrast, adult progenitor cells from the bone marrow of a healthy dog were able to recover fully following 9 days of culture in arginase. Over 3 days in culture, arginase was more effective than asparaginase in inducing the death of lymphoid lines. These results strongly suggest that short-term arginase treatment warrants further investigation as a therapy for lymphoid malignancies and osteosarcomas in dogs.
doi:10.1371/journal.pone.0054464
PMCID: PMC3554772  PMID: 23365669
11.  A comparison of the efficacy of transplantation of bone marrow-derived mesenchymal stem cells and unrestricted somatic stem cells on outcome after acute myocardial infarction 
Introduction
A number of questions remain unanswered in the field of cell therapy for acute myocardial infarction, including what is the optimal cell type, and can therapeutic efficacy be enhanced by conditioning regimens. In this study, we sought to address these questions by directly comparing the effect of bone marrow-derived mesenchymal stem cells and unrestricted somatic stem cells delivered 24 hours post-myocardial infarction and by determining if the therapeutic efficacy of unrestricted somatic stem cells could be enhanced by exposing the cells to guiding factors before cell transplantation.
Methods
Unrestricted somatic stem cells were guided by exposure to 50 ng/mL basic fibroblast growth factor, 20 ng/mL hepatocyte growth factor and 20 ng/mL bone morphogenetic protein-2 for 24 hours. Using a Sprague-Dawley rat model of acute myocardial infarction, we transplanted cells by intramyocardial injection 24 hours post-myocardial infarction. Cardiac function was serially measured using echocardiography, and histological analyses of infarct morphology, angiogenesis and apoptosis were obtained. Transcriptomic and proteomic changes were assessed using microarray and real-time quantitative PCR.
Results
When assessed 28 days after the myocardial infarction, the delivery of mesenchymal stem cells 24 hours post-myocardial infarction did not improve ejection fraction (P = 0.19), and did not prevent the decline in ejection fraction observed in the absence of cell therapy (P = 0.17). The administration of unrestricted somatic stem cells also did not improve ejection fraction (P = 0.11), but did prevent a further decline in ejection fraction (P = 0.001). Delivery of guided unrestricted somatic stem cells significantly improved ejection fraction (P = 0.03). Guided unrestricted somatic stem cells restored function to a greater extent than mesenchymal stem cells (P = 0.03). The infarct area (P = 0.2), apoptosis (P = 0.07) and angiogenesis (P = 0.09) did not differ between groups. Microarray analysis revealed that, following pre-implantation guiding, the gene groupings of mitosis, signalling and angiogenesis were highly overrepresented, mediators of apoptosis were overrepresented, and cardiomyocyte-associated genes were not differentially expressed.
Conclusions
These results suggest that guided unrestricted somatic stem cells have a moderate capacity to repair cardiac damage and that they are more effective than mesenchymal stem cells in restoring cardiac function after a myocardial infarction. The mechanism of the benefit was not fully elucidated in this study, but these observations may be mediated by favorable dysregulation of angiogenic and apoptotic gene groupings.
doi:10.1186/scrt127
PMCID: PMC3580427  PMID: 22974654
Cardiac failure; cardiac repair; guiding; mesenchymal stem cell; myocardial infarction; pre-conditioned; stem cell; umbilical cord; unrestricted somatic stem cell
12.  Enhanced Differentiation of Adult Bone Marrow-Derived Stem Cells to Liver Lineage in Aggregate Culture 
Tissue Engineering. Part A  2011;17(17-18):2331-2341.
Hepatocyte-like cells derived from stem cells hold great potential for clinical and pharmaceutical applications, including high-throughput drug toxicity screening. We report a three-dimensional aggregate culture system for the directed differentiation of adult rat bone marrow-derived stem cells, rat multipotent adult progenitor cells, to hepatocyte-like cells. Compared to adherent monolayer cultures, differentiation in the aggregate culture system resulted in significantly higher expression level of liver-specific transcripts, including an increased albumin mRNA level, and higher levels of albumin and urea secretion. This coincides with the presence of significantly more cells that express intracellular albumin at levels found in primary hepatocytes. The differentiated cell aggregates exhibited cytochrome P450-mediated ethoxyresorufin-O-dealkylation and pentoxyresorufin-O-dealkylation activity. Consistent with these increased mature functions, cells within the aggregates were shown to have many ultrastructural features of mature hepatocytes by transmission electron microscopy. With the scalability of the aggregate culture system and the enhanced differentiation capability, this system may facilitate translation of generating hepatocytes from stem cells to technology.
doi:10.1089/ten.tea.2010.0667
PMCID: PMC3161102  PMID: 21548835
13.  Adenoviral Transduction of Mesenchymal Stem Cells: In Vitro Responses and In Vivo Immune Responses after Cell Transplantation 
PLoS ONE  2012;7(8):e42662.
Adult mesenchymal stem cells (MSCs) are non-hematopoietic cells with multi-lineage potential which makes them attractive targets for regenerative medicine applications. However, to date, therapeutic success of MSC-therapy is limited and the genetic modification of MSCs using viral vectors is one option to improve their therapeutic potential. Ex-vivo genetic modification of MSCs using recombinant adenovirus (Ad) could be promising to reduce undesired immune responses as Ad will be removed before cell/tissue transplantation. In this regard, we investigated whether Ad-modification of MSCs alters their immunological properties in vitro and in vivo. We found that Ad-transduction of MSCs does not lead to up-regulation of major histocompatibility complex class I and II and co-stimulatory molecules CD80 and CD86. Moreover, Ad-transduction caused no significant changes in terms of pro-inflammatory cytokine expression, chemokine and chemokine receptor and Toll-like receptor expression. In addition, Ad-modification of MSCs had no affect on their ability to suppress T cell proliferation in vitro. In vivo injection of Ad-transduced MSCs did not change the frequency of various immune cell populations (antigen presenting cells, T helper and cytotoxic T cells, natural killer and natural killer T cells) neither in the blood nor in tissues. Our results indicate that Ad-modification has no major influence on the immunological properties of MSCs and therefore can be considered as a suitable gene vector for therapeutic applications of MSCs.
doi:10.1371/journal.pone.0042662
PMCID: PMC3412834  PMID: 22880073
15.  Typical investigational medicinal products follow relatively uniform regulations in 10 European Clinical Research Infrastructures Network (ECRIN) countries 
Trials  2012;13:27.
Background
In order to facilitate multinational clinical research, regulatory requirements need to become international and harmonised. The EU introduced the Directive 2001/20/EC in 2004, regulating investigational medicinal products in Europe.
Methods
We conducted a survey in order to identify the national regulatory requirements for major categories of clinical research in ten European Clinical Research Infrastructures Network (ECRIN) countries-Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and United Kingdom-covering approximately 70% of the EU population. Here we describe the results for regulatory requirements for typical investigational medicinal products, in the ten countries.
Results
Our results show that the ten countries have fairly harmonised definitions of typical investigational medicinal products. Clinical trials assessing typical investigational medicinal products require authorisation from a national competent authority in each of the countries surveyed. The opinion of the competent authorities is communicated to the trial sponsor within the same timelines, i.e., no more than 60 days, in all ten countries. The authority to which the application has to be sent to in the different countries is not fully harmonised.
Conclusion
The Directive 2001/20/EC defined the term 'investigational medicinal product' and all regulatory requirements described therein are applicable to investigational medicinal products. Our survey showed, however, that those requirements had been adopted in ten European countries, not for investigational medicinal products overall, but rather a narrower category which we term 'typical' investigational medicinal products. The result is partial EU harmonisation of requirements and a relatively navigable landscape for the sponsor regarding typical investigational medicinal products.
doi:10.1186/1745-6215-13-27
PMCID: PMC3338370  PMID: 22452964
16.  Exclusion of cytoplasmic fragments in flow cytometric analysis of lymph node samples from dogs with lymphoma using membrane-permeable violet laser-excitable DNA-binding fluorescent dye (DyeCycle Violet) 
Background
Cytoplasmic fragments derived from fragile neoplastic lymphocytes are common in samples of lymph nodes collected from dogs with lymphoma. These cytoplasmic fragments interfere with accurate gating of target cells and quantification protocols used for flow cytometry because of their variable size and expression of lymphoid cell surface antigens on their membranes.
Objective
The aim of this study was to develop a method to efficiently exclude cytoplasmic fragments from flow cytometric analysis of canine lymph nodes in which lymphoma was present.
Methods
Single-cell suspensions of neoplastic cells were prepared from biopsy samples and fine-needle aspirates of lymph nodes from 23 dogs with lymphoma. Suspensions were stained using a violet laser-excitable (405 nm) membrane-permeable DNA-binding fluorescent dye (DyeCycle Violet, DCV), incubated with antibodies against CD3, CD5, CD21, CD22, and CD45, and then stained with 7-amino-actinomycin D, an argon-excitable (488 nm) membrane-impermeable DNA-binding fluorescent dye. Multi-parameter flow cytometry was used for analysis based on selective uptake and laser-activated fluorescence of these dyes.
Results
Cytoplasmic fragments, which were DCV-negative and CD45-positive, and dead cells, which were positive for 7-amino-actinomycin D, were efficiently separated from neoplastic cells.
Conclusion
Staining with DyeCycle Violet is a useful method to improve flow cytometric gating methods and quantitative analyses of lymph node samples from dogs with lymphoma.
doi:10.1111/j.1939-165X.2010.00252.x
PMCID: PMC3065654  PMID: 21198735
Canine; flow cytometry; lymphoglandular bodies
17.  Functionalized scaffold mediated interleukin-10 gene delivery significantly improves survival rates of stem cells in vivo 
While stem cell transplantation could potentially treat a variety of disorders, clinical studies have not yet demonstrated conclusive benefits. This may be partly because transplanted stem cells have low survival rates, potentially due to host inflammation. The system described herein used two different gene therapy techniques to improve retention of rat mesenchymal stem cells. In the first, stem cells were transfected with interleukin-10 before being loaded into a collagen scaffold. In the second, unmodified stem cells were loaded into a collagen scaffold along with polymer-complexed interleukin-10 plasmids. The scaffolds were surgically implanted into the dorsum of syngeneic rats. At each endpoint, the scaffolds were explanted and cell retention, interleukin-10 level and inflammatory response were quantified. All treatment groups had statistically significant increases in cell retention after 7 days, but the group treated with 2 μg of interleukin-10 polyplexes had a significant improvement even at 21 days. This cell retention was associated with increased interleukin-10 and decreased levels of pro-inflammatory cytokines and apoptosis. The primary effect on the inflammatory response appeared to be on macrophage differentiation, encouraging the regulatory phenotype over the cytotoxic lineage. Improving cell survival may be an important step towards realization of the therapeutic potential of stem cells.
doi:10.1038/mt.2010.311
PMCID: PMC3086863  PMID: 21266957
18.  Advances in mesenchymal stem cell-mediated gene therapy for cancer 
Mesenchymal stem cells have a natural tropism for tumours and their metastases, and are also considered immunoprivileged. This remarkable combination of properties has formed the basis for many studies investigating their potential as tumour-specific delivery vehicles for suicide genes, oncolytic viruses and secreted therapeutic proteins. The aim of the present review is to discuss the range of approaches that have been used to exploit the tumour-homing capacity of mesenchymal stem cells for gene delivery, and to highlight advances required to realize the full potential of this promising approach.
doi:10.1186/scrt25
PMCID: PMC2941117  PMID: 20699014
19.  When a nephrectomy cures hypoglycaemia 
BMJ Case Reports  2009;2009:bcr0220091617.
A 40-year-old woman presented with a 10 day history of episodic vagueness, speech disturbance and blurred vision. Episodes typically occurred in the morning after awaking from sleep and resolved with food ingestion. She had no past medical history, did not drink alcohol and was not on any medication. Physical examination was normal with no evidence of endocrinopathy. After 10 h of fasting, she became hypoglycaemic with evidence of neuroglycopenia, which resolved with intravenous dextrose. Biochemical investigations revealed decreased glucose, insulin and C-peptide values with an increased excess insulin-like growth factor II: excess insulin-like growth factor I (IGF-II: IGF-I) ratio. Radiological examinations of the abdomen and pelvis revealed a heterogenous 10.5 cm left renal mass. The patient underwent a radical left nephrectomy. She had complete resolution of hypoglycaemic events. Histology revealed a renal sarcoma, grade 2/3. This is the first report in the literature involving a renal sarcoma causing non-islet cell tumour hypoglycaemia via excess IGF-II secretion.
doi:10.1136/bcr.02.2009.1617
PMCID: PMC3027856  PMID: 21687037
20.  Cognitive Recovery in the Aged Rat after Stroke and Anti-Nogo-A Immunotherapy 
Behavioural brain research  2009;208(2):415-424.
We have previously shown that immunotherapy directed against the protein Nogo-A leads to recovery on a skilled forelimb reaching task in rats after sensorimotor cortex stroke, which correlated with axonal and dendritic plasticity. Here we investigated anti-Nogo-A immunotherapy as an intervention to improve performance on a spatial memory task in aged rats after stroke, and whether cognitive recovery was correlated with structural plasticity. Aged rats underwent a unilateral distal permanent middle cerebral artery occlusion and one week later were treated with an anti-Nogo-A or control antibody. Nine weeks post-stroke, treated rats and normal aged rats were tested on the Morris water maze task. Following testing rats were sacrificed and brains processed for the Golgi-Cox method. Hippocampal CA3 and CA1 pyramidal and dentate gyrus granule cells were examined for dendritic length and number of branch segments, and CA3 and CA1 pyramidal cells were examined for spine density and morphology. Anti-Nogo-A immunotherapy given one week following stroke in aged rats improved performance on the reference memory portion of the Morris water maze task. However, this improved performance was not correlated with structural changes in the hippocampal neurons examined. Our finding of improved performance on the Morris water maze in aged rats after stroke and treatment with anti-Nogo-A immunotherapy demonstrates the promising therapeutic potential for anti-Nogo-A immunotherapy to treat cognitive deficits after stroke. The identification of sites of axonal and dendritic plasticity in the aged brain after stroke and treatment with anti-Nogo-A immunotherapy is still under investigation.
doi:10.1016/j.bbr.2009.12.015
PMCID: PMC2831114  PMID: 20035795
Nogo-A; Stroke; Aging; Navigation; Dendritic arborization; Dendritic spine
22.  Lentiviral vector mediated modification of mesenchymal stem cells & enhanced survival in an in vitro model of ischaemia 
Introduction
A combination of gene and cell therapies has the potential to significantly enhance the therapeutic value of mesenchymal stem cells (MSCs). The development of efficient gene delivery methods is essential if MSCs are to be of benefit using such an approach. Achieving high levels of transgene expression for the required period of time, without adversely affecting cell viability and differentiation capacity, is crucial. In the present study, we investigate lentiviral vector-mediated genetic modification of rat bone-marrow derived MSCs and examine any functional effect of such genetic modification in an in vitro model of ischaemia.
Methods
Transduction efficiency and transgene persistence of second and third generation rHIV-1 based lentiviral vectors were tested using reporter gene constructs. Use of the rHIV-pWPT-EF1-α-GFP-W vector was optimised in terms of dose, toxicity, cell species, and storage. The in vivo condition of ischaemia was modelled in vitro by separation into its associated constituent parts i.e. hypoxia, serum and glucose deprivation, in which the effect of therapeutic gene over-expression on MSC survival was investigated.
Results
The second generation lentiviral vector rHIV-pWPT-EF1-α-GFP-W, was the most efficient and provided the most durable transgene expression of the vectors tested. Transduction with this vector did not adversely affect MSC morphology, viability or differentiation potential, and transgene expression levels were unaffected by cryopreservation of transduced cells. Over-expression of HSP70 resulted in enhanced MSC survival and increased resistance to apoptosis in conditions of hypoxia and ischaemia. MSC differentiation capacity was significantly reduced after oxygen deprivation, but was preserved with HSP70 over-expression.
Conclusions
Collectively, these data validate the use of lentiviral vectors for efficient in vitro gene delivery to MSCs and suggest that lentiviral vector transduction can facilitate sustained therapeutic gene expression, providing an efficient tool for ex vivo MSC modification. Furthermore, lentiviral mediated over-expression of therapeutic genes in MSCs may provide protection in an ischaemic environment and enable MSCs to function in a regenerative manner, in part through maintaining the ability to differentiate. This finding may have considerable significance in improving the efficacy of MSC-based therapies.
doi:10.1186/scrt53
PMCID: PMC3226283  PMID: 21385372
23.  Signaling integration in the rugae growth zone directs sequential SHH signaling center formation during the rostral outgrowth of the palate 
Developmental biology  2009;336(1):53-67.
Evolution of facial morphology arises from variation in the activity of developmental regulatory networks that guide the formation of specific craniofacial elements. Importantly, the acquisition of novel morphology must be integrated with a phylogenetically inherited developmental program. We have identified a unique region of the secondary palate associated with the periodic formation of rugae during the rostral outgrowth of the face. Rugae function as SHH signaling centers to pattern the elongating palatal shelves. We have found that a network of signaling genes and transcription factors is spatially organized relative to palatal rugae. Additionally, the first formed ruga is strategically positioned at the presumptive junction of the future hard and soft palate that defines anterior-posterior differences in regional growth, mesenchymal gene expression and cell fate. We propose a molecular circuit integrating FGF and BMP signaling to control proliferation and differentiation during the sequential formation of rugae and inter-rugae domains in the palatal epithelium. The loss of p63 and Sostdc1 expression and failed rugae differentiation highlight that coordinated epithelial mesenchymal signaling is lost in the Fgf10 mutant palate. Our results establish a genetic program that reiteratively organizes signaling domains to coordinate the growth of the secondary palate with the elongating midfacial complex.
doi:10.1016/j.ydbio.2009.09.028
PMCID: PMC2789450  PMID: 19782673
craniofacial evolution; palate development; periodic patterning; developmental module; signaling network; FGF; BMP; SHH; p63
24.  Current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury using polymer scaffolds☆ 
This review highlights current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury. The concept of developing 3-dimensional polymer scaffolds for placement into a spinal cord transection model has recently been more extensively explored as a solution for restoring neurologic function after injury. Given the patient morbidity associated with respiratory compromise, the discrete tracts in the spinal cord conveying innervation for breathing represent an important and achievable therapeutic target. The aim is to derive new neuronal tissue from the surrounding, healthy cord that will be guided by the polymer implant through the injured area to make functional reconnections. A variety of naturally derived and synthetic biomaterial polymers have been developed for placement in the injured spinal cord. Axonal growth is supported by inherent properties of the selected polymer, the architecture of the scaffold, permissive microstructures such as pores, grooves or polymer fibres, and surface modifications to provide improved adherence and growth directionality. Structural support of axonal regeneration is combined with integrated polymeric and cellular delivery systems for therapeutic drugs and for neurotrophic molecules to regionalize growth of specific nerve populations.
doi:10.1016/j.resp.2009.08.015
PMCID: PMC2981799  PMID: 19737633
Spinal cord injury; Axonal regeneration; Polymer scaffold; Tissue engineering; Neurotrophins
25.  Compassionate use of interventions: results of a European Clinical Research Infrastructures Network (ECRIN) survey of ten European countries 
Trials  2010;11:104.
Background
'Compassionate use' programmes allow medicinal products that are not authorised, but are in the development process, to be made available to patients with a severe disease who have no other satisfactory treatment available to them. We sought to understand how such programmes are regulated in ten European Union countries.
Methods
The European Clinical Research Infrastructures Network (ECRIN) conducted a comprehensive survey on clinical research regulatory requirements, including questions on regulations of 'compassionate use' programmes. Ten European countries, covering approximately 70% of the EU population, were included in the survey (Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the UK).
Results
European Regulation 726/2004/EC is clear on the intentions of 'compassionate use' programmes and aimed to harmonise them in the European Union. The survey reveals that different countries have adopted different requirements and that 'compassionate use' is not interpreted in the same way across Europe. Four of the ten countries surveyed have no formal regulatory system for the programmes. We discuss the need for 'compassionate use' programmes and their regulation where protection of patients is paramount.
Conclusions
'Compassionate use' is a misleading term and should be replaced with 'expanded access'. There is a need for expanded access programmes in order to serve the interests of seriously ill patients who have no other treatment options. To protect these patients, European legislation needs to be more explicit and informative with regard to the regulatory requirements, restrictions, and responsibilities in expanded access programmes.
doi:10.1186/1745-6215-11-104
PMCID: PMC2997627  PMID: 21073691

Results 1-25 (43)