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Find video protocols related to scientific articles indexed in Pubmed.
Emerging roles of extracellular vesicles in the nervous system.
J. Neurosci.
PUBLISHED: 11-14-2014
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Information exchange executed by extracellular vesicles, including exosomes, is a newly described form of intercellular communication important in the development and physiology of neural systems. These vesicles can be released from cells, are packed with information including signaling proteins and both coding and regulatory RNAs, and can be taken up by target cells, thereby facilitating the transfer of multilevel information. Recent studies demonstrate their critical role in physiological processes, including nerve regeneration, synaptic function, and behavior. These vesicles also have a sinister role in the propagation of toxic amyloid proteins in neurodegenerative conditions, including prion diseases and Alzheimer's and Parkinson's diseases, in inducing neuroinflammation by exchange of information between the neurons and glia, as well as in aiding tumor progression in the brain by subversion of normal cells. This article provides a summary of topics covered in a symposium and is not meant to be a comprehensive review of the subject.
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The cyclic AMP pathway is a sex-specific modifier of glioma risk in type 1 neurofibromatosis patients.
Cancer Res.
PUBLISHED: 11-09-2014
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Identifying modifiers of glioma risk in patients with type 1 neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis and potentially identify novel therapeutic targets. Here we report genetic polymorphisms in the human adenylate cyclase gene ADCY8 which correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.
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Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort.
Pharmacogenet. Genomics
PUBLISHED: 11-08-2014
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The efficacy of statins, which are used commonly in primary and secondary prevention of cardiovascular diseases, shows a wide range of interindividual variability. Genetic variants of OATP1B1, a hepatic uptake transporter, can modify access of statins to its therapeutic target, thereby potentially altering drug efficacy. We studied the impact of genetic variants of OATP1B1 on the lipid-lowering efficacy of statins in a population-based setting.
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Relative Femoral Neck Lengthening Improves Pain and Hip Function in Proximal Femoral Deformities With a High-riding Trochanter.
Clin. Orthop. Relat. Res.
PUBLISHED: 11-07-2014
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Complex proximal femoral deformities, including an elevated greater trochanter, short femoral neck, and aspherical head-neck junction, often result in pain and impaired hip function resulting from intra-/extraarticular impingement. Relative femoral neck lengthening may address these deformities, but mid-term results of this approach have not been widely reported.
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REFERENCE VALUES FOR LEPTIN, CORTISOL, INSULIN AND GLUCOSE, AMONG EUROPEAN ADOLESCENTS AND THEIR ASSOCIATION WITH ADIPOSITY: THE HELENA STUDY.
Nutr Hosp
PUBLISHED: 11-04-2014
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Adequate concentrations of leptin, cortisol, and insulin are important for a suitable metabolism and development during adolescence. These hormones jointly with glucose play a major role in fat metabolism and development of childhood obesity. Our main objective was to quantify biomarkers as leptin, cortisol, insulin and glucose status in European adolescents to contribute to establish reference ranges.
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Weak ergodicity breaking and aging of chaotic transport in hamiltonian systems.
Phys. Rev. Lett.
PUBLISHED: 10-31-2014
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Momentum diffusion is a widespread phenomenon in generic Hamiltonian systems. We show for the prototypical standard map that this implies weak ergodicity breaking for the superdiffusive transport in coordinate direction with an averaging-dependent quadratic and cubic increase of the mean-squared displacement (MSD), respectively. This is explained via integrated Brownian motion, for which we derive aging time dependent expressions for the ensemble-averaged MSD, the distribution of time-averaged MSDs, and the ergodicity breaking parameter. Generalizations to other systems showing momentum diffusion are pointed out.
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Task-Driven Evaluation of Aggregation in Time Series Visualization.
Proc SIGCHI Conf Hum Factor Comput Syst
PUBLISHED: 10-25-2014
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Many visualization tasks require the viewer to make judgments about aggregate properties of data. Recent work has shown that viewers can perform such tasks effectively, for example to efficiently compare the maximums or means over ranges of data. However, this work also shows that such effectiveness depends on the designs of the displays. In this paper, we explore this relationship between aggregation task and visualization design to provide guidance on matching tasks with designs. We combine prior results from perceptual science and graphical perception to suggest a set of design variables that influence performance on various aggregate comparison tasks. We describe how choices in these variables can lead to designs that are matched to particular tasks. We use these variables to assess a set of eight different designs, predicting how they will support a set of six aggregate time series comparison tasks. A crowd-sourced evaluation confirms these predictions. These results not only provide evidence for how the specific visualizations support various tasks, but also suggest using the identified design variables as a tool for designing visualizations well suited for various types of tasks.
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Visualizing Validation of Protein Surface Classifiers.
Comput Graph Forum
PUBLISHED: 10-25-2014
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Many bioinformatics applications construct classifiers that are validated in experiments that compare their results to known ground truth over a corpus. In this paper, we introduce an approach for exploring the results of such classifier validation experiments, focusing on classifiers for regions of molecular surfaces. We provide a tool that allows for examining classification performance patterns over a test corpus. The approach combines a summary view that provides information about an entire corpus of molecules with a detail view that visualizes classifier results directly on protein surfaces. Rather than displaying miniature 3D views of each molecule, the summary provides 2D glyphs of each protein surface arranged in a reorderable, small-multiples grid. Each summary is specifically designed to support visual aggregation to allow the viewer to both get a sense of aggregate properties as well as the details that form them. The detail view provides a 3D visualization of each protein surface coupled with interaction techniques designed to support key tasks, including spatial aggregation and automated camera touring. A prototype implementation of our approach is demonstrated on protein surface classifier experiments.
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[Cancer stem cell phenotypes and miRNA : Therapeutic targets in head and neck squamous cell carcinoma.]
HNO
PUBLISHED: 10-23-2014
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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. HNSCC is caused by persistent high-risk human papillomavirus (HR-HPV) infection or excessive consumption of alcohol or tobacco. The persistently low survival rates result from local recurrences and metastases, which are probably caused by so-called tumor stem cells (TSCs). The epithelial-mesenchymal transition (EMT) or transformation is a key event in metastasis initiation and is being increasingly associated with TSCs.
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Transcranial Laser Therapy in Acute Stroke Treatment: Results of Neurothera Effectiveness and Safety Trial 3, a Phase III Clinical End Point Device Trial.
Stroke
PUBLISHED: 10-07-2014
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On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke.
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GP130 activation induces myeloma and collaborates with MYC.
J. Clin. Invest.
PUBLISHED: 10-03-2014
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Multiple myeloma (MM) is a plasma cell neoplasm that results from clonal expansion of an Ig-secreting terminally differentiated B cell. Advanced MM is characterized by tissue damage that involves bone, kidney, and other organs and is typically associated with recurrent genetic abnormalities. IL-6 signaling via the IL-6 signal transducer GP130 has been implicated as an important driver of MM pathogenesis. Here, we demonstrated that ectopic expression of constitutively active GP130 (L-GP130) in a murine retroviral transduction-transplantation model induces rapid MM development of high penetrance. L-GP130-expressing mice recapitulated all of the characteristics of human disease, including monoclonal gammopathy, BM infiltration with lytic bone lesions, and protein deposition in the kidney. Moreover, the disease was easily transplantable and allowed different therapeutic options to be evaluated in vitro and in vivo. Using this model, we determined that GP130 signaling collaborated with MYC to induce MM and was responsible and sufficient for directing the plasma cell phenotype. Accordingly, we identified Myc aberrations in the L-GP130 MM model. Evaluation of human MM samples revealed recurrent activation of STAT3, a downstream target of GP130 signaling. Together, our results indicate that deregulated GP130 activity contributes to MM pathogenesis and that pathways downstream of GP130 activity have potential as therapeutic targets in MM.
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Multiple mechanisms mediate resistance to sorafenib in urothelial cancer.
Int J Mol Sci
PUBLISHED: 09-25-2014
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Genetic and epigenetic changes in the mitogen activated protein kinase (MAPK) signaling render urothelial cancer a potential target for tyrosine kinase inhibitor (TKI) treatment. However, clinical trials of several TKIs failed to prove efficacy. In this context, we investigated changes in MAPK signaling activity, downstream apoptotic regulators and changes in cell cycle distribution in different urothelial cancer cell lines (UCCs) upon treatment with the multikinase inhibitor sorafenib. None of the classical sorafenib targets (vascular endothelial growth factor receptor 1/-receptor 2, VEGFR1/-R2; platelet-derived growth factor receptor ?/-receptor ?, PDGFR-?/-?; c-KIT) was expressed at significant levels leaving RAF proteins as its likely molecular target. Low sorafenib concentrations paradoxically increased cell viability, whereas higher concentrations induced G1 arrest and eventually apoptosis. MAPK signaling remained partly active after sorafenib treatment, especially in T24 cells with an oncogenic HRAS mutation. AKT phosphorylation was increased, suggesting compensatory activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Sorafenib regularly down regulated the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) protein, but combinatorial treatment with ABT-737 targeting other B-cell lymphoma 2 (Bcl-2) family proteins did not result in synergistic effects. In summary, efficacy of sorafenib in urothelial cancer cell lines appears hampered by limited effects on MAPK signaling, crosstalk with further cancer pathways and an anti-apoptotic state of UCCs. These observations may account for the lack of efficacy of sorafenib in clinical trials and should be considered more broadly in the development of signaling pathway inhibitors for drug therapy in urothelial carcinoma.
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Prognostic significance of overexpressed p16INK4a in patients with cervical cancer: a meta-analysis.
PLoS ONE
PUBLISHED: 09-04-2014
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p16INK4a is a tumor suppressor protein which is induced in cells upon the interaction of high-risk HPV E7 with the retinoblastoma protein by a positive feedback loop, but cannot exert its suppressing effect. Previous reports suggested that p16INK4a immunostaining allows precise identification of even small CIN or cervical cancer lesions in biopsies. The prognostic value of overexpressed p16INK4a in cervical cancer has been evaluated for several years while the results remain controversial. We performed a systematic review and meta-analysis of studies assessing the clinical and prognostic significance of overexpression of p16INK4a in cervical cancer.
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miR-21 increases the programmed cell death 4 gene-regulated cell proliferation in head and neck squamous carcinoma cell lines.
Oncol. Rep.
PUBLISHED: 09-01-2014
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MicroRNAs (miRs) are small non-coding RNAs that regulate the translation of many genes in normal and cancer cells where they are frequently dysregulated promoting tumor progression. Several studies have illustrated the potential of manipulating miR expression in cancer research and therapy. The aim of the present study was to investigate expression patterns of a panel of miRs in head and neck squamous cell carcinoma (HNSCC) shown to be relevant in other carcinomas and to elucidate their role if dysregulated. We performed analysis of miR?21, -200c, -138-1, -138-2, -25 and -34 expression by qRT-PCR in 6 HNSCC cell lines and computerized search for genetic targets of dysregulated miRNA-21 (miR?21). Lipofection of mock and anti-miR-21 and determination of expression efficiencies and final programmed cell death 4 (PDCD4) expression were carried out by luciferase assay and western blotting. MTT assay was used to measure cell proliferation and flow cytometry was performed for cell cycle analysis. Expression of miR-21 was most prominently upregulated in the HNSCC cell lines, particularly in UM-SCC11B (6.45±0.25-fold, P<0.05) and UM-SCC9 (4.35±0.22-fold, P<0.05) as compared to primary epidermal keratinocytes used as control. The expression levels of the other miRs showed no difference except for miR-34 and -138-1 each in one cell line. Subsequent transfection of precursor miR-21 stimulated proliferation while anti-miR-21 inhibited proliferation of both cell lines. PDCD4 was identified with software designed for this purpose as potential target gene of miR-21. Subsequently, its role in HNSCC lines was experimentally confirmed by regulation of PDCD4 transfecting miR-21 mimics and anti-miR-21. Finally, we showed that PDCD4 is negatively regulated by miR-21 at the post-transcriptional level via binding to the 3'-untranslated region of PDCD4 mRNA. A role of upregulated miR-21 and reduced PDCD4 stimulating the proliferation was demonstrated in HNSCC lines and, in turn, transfection of anti-miR-21 upregulating PDCD4 reduced the cellular division rate. We explored miR-21 and PDCD4 expression as markers of progression and prognosis and for a potential translational value in the development of agents slowing growth of HNSCC and other carcinomas useful in palliative therapy or as a component of multi-modality treatments.
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Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation.
Philos. Trans. R. Soc. Lond., B, Biol. Sci.
PUBLISHED: 08-20-2014
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Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell-cell communication in the nervous system. We have shown that exosomes released from oligodendrocytes upon stimulation with the neurotransmitter glutamate are internalized by neurons and enhance the neuronal stress tolerance. Here, we demonstrate that oligodendroglial exosomes also promote neuronal survival during oxygen-glucose deprivation, a model of cerebral ischaemia. We show the transfer from oligodendrocytes to neurons of superoxide dismutase and catalase, enzymes which are known to help cells to resist oxidative stress. Additionally, we identify various effects of oligodendroglial exosomes on neuronal physiology. Electrophysiological analysis using in vitro multi-electrode arrays revealed an increased firing rate of neurons exposed to oligodendroglial exosomes. Moreover, gene expression analysis and phosphorylation arrays uncovered differentially expressed genes and altered signal transduction pathways in neurons after exosome treatment. Our study thus provides new insight into the broad spectrum of action of oligodendroglial exosomes and their effects on neuronal physiology. The exchange of extracellular vesicles between neural cells may exhibit remarkable potential to impact brain performance.
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Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.
Lancet
PUBLISHED: 08-05-2014
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Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase.
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CT Perfusion Imaging in the Selection of Acute Stroke Patients to Undergo Emergent Carotid Endarterectomy.
Ann Vasc Surg
PUBLISHED: 07-21-2014
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Severe acute stroke patients with critical carotid stenosis or occlusion without intracranial thrombus typically do not undergo emergent carotid thromboendarterectomy (CEA) because of the risk of reperfusion-related intracranial hemorrhage. Past studies have not consistently demonstrated benefit of early operative intervention. Cerebral computed tomography (CT), cervical and cerebral CT angiography (CTA), and cerebral CT perfusion (CTP) imaging may identify a subset of acute stroke patients without intracranial thrombus who may benefit from emergent CEA. Acute stroke patients underwent unenhanced brain CT imaging to exclude pathology that would contraindicate emergent therapy. Emergent CTAs of the intracranial and extracranial vessels were utilized to identify patients that presented with stroke symptoms based on the presence of isolated extracranial carotid disease in the absence of intracranial thromboembolism. CTP was then utilized to assess the extent of potentially reversible cerebral ischemia (penumbral tissue). Patients with isolated extracranial carotid lesions with significant reversible ischemia in the absence of large areas of irreversible cerebral damage underwent emergent CEA to salvage ischemic penumbra. In one year, three patients presented with large acute strokes in which CTA disclosed symptomatic extracranial internal carotid artery (ICA) pre-occlusive or occlusive lesions without intracranial thromboembolic occlusions. CTP indicated a large area of ischemic penumbra with limited permanent injury. Mean age, time to presentation, and National Institutes of Health stroke score (NIHSS) were 66 years, 4.2 hours, and 19.3. All underwent emergent CEA with cervical carotid thrombectomy. Average time from stroke symptom onset to revascularization was 10.5 (range 5.8-19.0) hours. There were no perioperative deaths. At day 5, the mean NIHSS decreased to 7.6 and at day 30 was 4.7. The modified Rankin scale score dropped from a post-stroke, pre-op level of 5 to 2.3 by day 30. Emergent CEA should be considered in patients presenting with large acute strokes based on favorable CT, CTA, and CTP findings. Emergent clot localization and physiological assessment of brain "tissue at risk" relative to irreversible cerebral infarction utilizing CT, CTA, and CTP is now available. Utilization of this information by an experienced stroke team of neurologists, radiologists, and surgeons may aid in the recognition of a select group of patients in which emergent CEA may drive to improved outcomes.
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Pittsburgh outcomes after stroke thrombectomy score predicts outcomes after endovascular therapy for anterior circulation large vessel occlusions.
Stroke
PUBLISHED: 07-08-2014
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Prognostication tools that predict good outcome in patients with anterior circulation large vessel occlusions after endovascular therapy are lacking. We aim to develop a tool that incorporates clinical and imaging data to predict outcomes after endovascular therapy.
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Suffering in children: opinions from parents and health-care professionals.
Eur. J. Pediatr.
PUBLISHED: 07-02-2014
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Alleviation of suffering is considered to be one of the important goals of medical interventions. Understanding of what constitutes suffering in children admitted to a pediatric intensive care unit (PICU) is lacking. This study aims to assess perceptions by parents, doctors, and nurses of suffering in critically ill children. We interviewed 124 participants (parents, physicians, and PICU nurses) caring for 29 admitted children in a 20-bed level-III PICU and performed a qualitative analysis. We found that most participants made a distinction between physical and existential suffering. Parents considered the child's suffering caused by or associated with visible signs as discomfort. Nurses linked suffering to the child's state of comfort. Physicians linked them to the intensity and impact of treatment and future perspectives of the child. Various aspects of the child's suffering and admission to a PICU caused suffering in parents. Conclusion: Parents', physicians', and nurses' perceptions of suffering overlap but also show important differences. Differences found seem to be rooted in the relation to and kind of responsibility (parental/professional) for the child. The child's illness, suffering, and hospital admission cause suffering in parents. Health-care professionals in PICUs need to be aware of these phenomena.
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Sequential treatment with taxanes and novel anti-androgenic compounds in castration-resistant prostate cancer.
Oncol Res Treat
PUBLISHED: 06-10-2014
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Several novel therapeutic agents have demonstrated ability to improve overall survival in metastatic castration-resistant prostate cancer (mCRPC) in recent years. With as many as 5 new agents approved within the last 5 years and an ongoing lack of comparative and prospective data, strategies for patient selection and sequencing of drug treatments are urgently needed. This review will summarize current clinical evidence and relevant molecular mechanisms in mCRPC. The understanding of these mechanisms may provide valuable assistance in making therapeutic decisions, especially while robust clinical data remain sparse.
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A comprehensively characterized large panel of head and neck cancer patient-derived xenografts identifies the mTOR inhibitor everolimus as potential new treatment option.
Int. J. Cancer
PUBLISHED: 06-08-2014
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Patient-derived xenograft (PDX) models have shown to reflect original patient tumors better than any other preclinical model. We embarked in a study establishing a large panel of head and neck squamous cell carcinomas PDX for biomarker analysis and evaluation of established and novel compounds. Out of 115 transplanted specimens 52 models were established of which 29 were characterized for response to docetaxel, cetuximab, methotrexate, carboplatin, 5-fluorouracil and everolimus. Further, tumors were subjected to sequencing analysis and gene expression profiling of selected mTOR pathway members. Most frequent response was observed for docetaxel and cetuximab. Responses to carboplatin, 5-fluorouracil and methotrexate were moderate. Everolimus revealed activity in the majority of PDX. Mutational profiling and gene expression analysis did not reveal a predictive biomarker for everolimus even though by trend RPS6KB1 mRNA expression was associated with response. In conclusion we demonstrate a comprehensively characterized panel of head and neck cancer PDX models, which represent a valuable and renewable tissue resource for evaluation of novel compounds and associated biomarkers. This article is protected by copyright. All rights reserved.
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Predictors of functional dependence despite successful revascularization in large-vessel occlusion strokes.
Stroke
PUBLISHED: 05-29-2014
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High revascularization rates in large-vessel occlusion strokes treated by mechanical thrombectomy are not always associated with good clinical outcomes. We evaluated predictors of functional dependence despite successful revascularization among patients with acute ischemic stroke treated with thrombectomy.
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Prospective Evaluation of Magnetic Resonance Imaging Guided In-bore Prostate Biopsy versus Systematic Transrectal Ultrasound Guided Prostate Biopsy in Biopsy Naïve Men with Elevated Prostate Specific Antigen.
J. Urol.
PUBLISHED: 05-16-2014
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Magnetic resonance imaging guided biopsy is increasingly performed to diagnose prostate cancer. However, there is a lack of well controlled, prospective trials to support this treatment method. We prospectively compared magnetic resonance imaging guided in-bore biopsy with standard systematic transrectal ultrasound guided biopsy in biopsy naïve men with increased prostate specific antigen.
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TIA triage in emergency department using acute MRI (TIA-TEAM): A feasibility and safety study.
Int J Stroke
PUBLISHED: 05-12-2014
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Positive diffusion weighted imaging (DWI) on MRI is associated with increased recurrent stroke risk in TIA patients. Acute MRI aids in TIA risk stratification and diagnosis.
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Incorporation of RANKL promotes osteoclast formation and osteoclast activity on ?-TCP ceramics.
Bone
PUBLISHED: 05-12-2014
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?-Tricalcium phosphate (?-TCP) ceramics are approved for the repair of osseous defects. In large defects, however, the substitution of the material by authentic bone is inadequate to provide sufficient long-term mechanical stability. We aimed to develop composites of ?-TCP ceramics and receptor activator of nuclear factor ?-B ligand (RANKL) to enhance the formation of osteoclasts and promote cell mediated calcium phosphate resorption. RANKL was adsorbed superficially onto ?-TCP ceramics or incorporated into a crystalline layer of calcium phosphate by the use of a co-precipitation technique. Murine osteoclast precursors were seeded onto the ceramics. After 15days, the formation of osteoclasts was quantified cytologically and colorimetrically with tartrate-resistant acidic phosphatase (TRAP) staining and TRAP activity measurements, respectively. Additionally, the expression of transcripts encoding the osteoclast gene products cathepsin K, calcitonin receptor, and of the sodium/hydrogen exchanger NHA2 were quantified by real-time PCR. The activity of newly formed osteoclasts was evaluated by means of a calcium phosphate resorption assay. Superficially adsorbed RANKL did not induce the formation of osteoclasts on ?-TCP ceramics. When co-precipitated onto ?-TCP ceramics RANKL supported the formation of mature osteoclasts. The development of osteoclast lineage cells was further confirmed by the increased expression of cathepsin K, calcitonin receptor, and NHA2. Incorporated RANKL stimulated the cells to resorb crystalline calcium phosphate. Our in vitro study shows that RANKL incorporated into ?-TCP ceramics induces the formation of active, resorbing osteoclasts on the material surface. Once formed, osteoclasts mediate the release of RANKL thereby perpetuating their differentiation and activation. In vivo, the stimulation of osteoclast-mediated resorption may contribute to a coordinated sequence of material resorption and bone formation. Further in vivo studies are needed to confirm the current in vitro findings.
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A Pilot Study for Evaluation of Hypotonia in Children With Neurofibromatosis Type 1.
J. Child Neurol.
PUBLISHED: 05-03-2014
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There are currently no objective criteria to evaluate pediatric hypotonia. The purpose of this pilot study was to identify diagnostic criteria for assessing hypotonia in children with neurofibromatosis type 1. Fifty-five subjects between the ages of 1 and 7 years with a diagnosis of neurofibromatosis type 1 were evaluated. A physical therapist recorded a subjective tone assessment and objective tone metrics, including ankle dorsiflexion, knee extension, hip abduction, triceps fat percentage, grip strength, and head lag during a pull-to-sit test. Multivariate logistic regression analysis showed the presence of head lag paired with increased hip range of motion was a significant predictor of hypotonia. The presence of head lag on a pull-to-sit test paired with increased hip range of motion is an accurate predictor of hypotonia in children with neurofibromatosis type 1. These objective measures should be prospectively evaluated in other pediatric populations for their ability to predict hypotonia.
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Prognostic value of a cell-cycle progression score in men with prostate cancer managed with active surveillance after MRI-guided prostate biopsy--a pilot study.
Anticancer Res.
PUBLISHED: 04-30-2014
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Initial inaccurate staging is a common problem associated with active surveillance (AS) for patients detected by transrectal ultrasound-guided prostate biopsy (TRUS-GB). Subsequently, repeated biopsies are necessary to monitor such patients. Thus, in addition to the already established clinicopathological criteria, there is a considerable demand for new, objective decision criteria to more accurately select AS candidates. Recently, a novel RNA expression signature derived from 31 cell-cycle progression (CCP) genes has been shown to be a strong predictor of outcome in patients after radical prostatectomy or radiotherapy. This is a qualitative pilot study to evaluate the prognostic value of the CCP-score (CCP-S) for the first time in men managed with AS after MRI-guided prostate biopsy (MRI-GB).
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Degarelix as an intermittent androgen deprivation therapy for one or more treatment cycles in patients with prostate cancer.
Eur. Urol.
PUBLISHED: 04-23-2014
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Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients.
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Diagnosis and management of developmental dysplasia of the hip from triradiate closure through young adulthood.
Instr Course Lect
PUBLISHED: 04-12-2014
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The current treatment of painful hip dysplasia in the mature skeleton is based on acetabular reorientation. Reorientation procedures attempt to optimize the anatomic position of the hyaline cartilage of the femoral head and acetabulum in regard to mechanical loading. Because the Bernese periacetabular osteotomy is a versatile technique for acetabular reorientation, it is helpful to understand the approach and be familiar with the criteria for an optimal surgical correction. The femoral side bears stigmata of hip dysplasia that may require surgical correction. Improvement of the head-neck offset to avoid femoroacetabular impingement has become routine in many hips treated with periacetabular osteotomy. In addition, intertrochanteric osteotomies can help improve joint congruency and normalize the femoral neck orientation. Other new surgical techniques allow trimming or reducing a severely deformed head, performing a relative neck lengthening, and trimming or distalizing the greater trochanter. ?An increasing number of studies have reported good long-term results after acetabular reorientation procedures, with expected joint preservation rates ranging from 80% to 90% at the 10-year follow-up and 60% to 70% at the 20-year follow-up. An ideal candidate is younger than 30 years, with no preoperative signs of osteoarthritis. Predicted joint preservation in these patients is approximately 90% at the 20-year follow-up. Recent evidence indicates that additional correction of an aspheric head may further improve results.
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Perioperative complications and oncological safety of robot-assisted (RARC) vs. open radical cystectomy (ORC).
Urol. Oncol.
PUBLISHED: 03-06-2014
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To assess the surgical and oncological outcome of robot-assisted radical cystectomy (RARC) compared with open radical cystectomy (ORC).
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MR-sequences for prostate cancer diagnostics: validation based on the PI-RADS scoring system and targeted MR-guided in-bore biopsy.
Eur Radiol
PUBLISHED: 03-05-2014
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This study evaluated the accuracy of MR sequences [T2-, diffusion-weighted, and dynamic contrast-enhanced (T2WI, DWI, and DCE) imaging] at 3T, based on the European Society of Urogenital Radiology (ESUR) scoring system [Prostate Imaging Reporting and Data System (PI-RADS)] using MR-guided in-bore prostate biopsies as reference standard.
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[Role of miRNA in malignoma of the head and neck].
Laryngorhinootologie
PUBLISHED: 02-27-2014
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Despite optimized therapeutic strategies, the long-term survival of head and neck squamous cell carcinomas (HNSCC) has improved in recent years only slightly. Most studies on the tumor cell genome focus on protein-coding genes (exons). Data on changes within the non-coding sequences (introns) are limited. miRNAs (microRNA, miR) are small non-coding single-stranded RNAs that control gene expression at the posttranscriptional level by interacting with the mRNA. miRNA functions include many biological processes and control up to 50 % of human genes. They can have oncogenic or tumor suppressive functions. Altered expression patterns of miRNAs are involved in carcinogenesis and tumor progression even in HNSCC, or those processes (increased resistance to radiation or chemotherapy) that could be responsible for the poor long-term prognosis by forming metastases and inoperable local recurrences. Therefore, we here present miRNA groups, which are involved in these processes and may serve as new potential therapeutic treatment targets. miRNAs may also serve as biomarkers for early diagnosis, evaluation and monitoring of treatment and tumor recurrence. Alterations in miRNA expression before and after chemotherapy are therefore of high interest. In the long run, this knowledge could lead to more effective therapies with improved therapeutic outcome of HNSCC.
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Prognostic significance of ALDH1A1-positive cancer stem cells in patients with locally advanced, metastasized head and neck squamous cell carcinoma.
J. Cancer Res. Clin. Oncol.
PUBLISHED: 02-22-2014
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Aldehyde dehydrogenase 1 (ALDH1A1) has now been recognized as a cancer stem(-like) cells (CSCs) marker in various tumors including head and neck squamous cell carcinoma (HNSCC). The objective of this study was to examine the expression of ALDH1A1 in patients with locally advanced, metastasized HNSCC and to determine its prognostic value.
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Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts.
Nat Commun
PUBLISHED: 02-20-2014
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The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.
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Training satisfaction and work environment in Otorhinolaryngology, Head and Neck surgery: a comparison between France and Germany.
Eur Arch Otorhinolaryngol
PUBLISHED: 02-12-2014
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With the coalescing of Europe, increased mobility of professionals emerges. Initiatives to harmonize medical education were launched. In Otolaryngology, Head and Neck surgery (ORL) an European board examination was created to ensure standards. Quality of training, satisfaction and quality of life of residents and recent ORL specialists were compared to assess different aspects of work and hierarchical relationships in France (FRA) and Germany (GER) by means of an anonymous questionnaire. 120 FRA and 125 GER questionnaires were included. 78 % of respondents were residents. 86 % would choose the same training again. In both countries, a majority felt well considered with responsibilities adapted to their level of training and with supportive supervisors. Germans reported average daily work hours of 9.6 versus 11 in FRA with compensated overtime (76 %) and a possibility of part-time work (62 %), both nearly inexistent in FRA. In GER, the day-off after duty was more often respected. French attributed their seniors better pedagogic skills, taking time for explanations and providing better teaching. Offering a good training was a more important objective in French training centers (77 vs. 51 %). In both countries, surgical training relied on coaching. Research activities were comparable. The overall satisfaction with ORL training was high. Differences concerned structure of training, guidance by senior doctors and the working conditions. The study results provide guidance before choosing a program and may help to improve current training by identifying positive aspects that, if combined could lead to a convergence of programs. However, present high standards of education must be maintained.
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German second-opinion network for testicular cancer: sealing the leaky pipe between evidence and clinical practice.
Oncol. Rep.
PUBLISHED: 01-28-2014
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In 2006, the German Testicular Cancer Study Group initiated an extensive evidence-based national second-opinion network to improve the care of testicular cancer patients. The primary aims were to reflect the current state of testicular cancer treatment in Germany and to analyze the project's effect on the quality of care delivered to testicular cancer patients. A freely available internet-based platform was developed for the exchange of data between the urologists seeking advice and the 31 second-opinion givers. After providing all data relevant to the primary treatment decision, urologists received a second opinion on their therapy plan within <48 h. Endpoints were congruence between the first and second opinion, conformity of applied therapy with the corresponding recommendation and progression-free survival rate of the introduced patients. Significance was determined by two-sided Pearson's ?2 test. A total of 1,284 second-opinion requests were submitted from November 2006 to October 2011, and 926 of these cases were eligible for further analysis. A discrepancy was found between first and second opinion in 39.5% of the cases. Discrepant second opinions led to less extensive treatment in 28.1% and to more extensive treatment in 15.6%. Patients treated within the framework of the second-opinion project had an overall 2-year progression-free survival rate of 90.4%. Approximately every 6th second opinion led to a relevant change in therapy. Despite the lack of financial incentives, data from every 8th testicular cancer patient in Germany were submitted to second-opinion centers. Second-opinion centers can help to improve the implementation of evidence into clinical practice.
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Axon-glia interaction and membrane traffic in myelin formation.
Front Cell Neurosci
PUBLISHED: 01-06-2014
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In vertebrate nervous systems myelination of neuronal axons has evolved to increase conduction velocity of electrical impulses with minimal space and energy requirements. Myelin is formed by specialized glial cells which ensheath axons with a lipid-rich insulating membrane. Myelination is a multi-step process initiated by axon-glia recognition triggering glial polarization followed by targeted myelin membrane expansion and compaction. Thereby, a myelin sheath of complex subdomain structure is established. Continuous communication between neurons and glial cells is essential for myelin maintenance and axonal integrity. A diverse group of diseases, from multiple sclerosis to schizophrenia, have been linked to malfunction of myelinating cells reflecting the physiological importance of the axon-glial unit. This review describes the mechanisms of axonal signal integration by oligodendrocytes emphasizing the central role of the Src-family kinase Fyn during central nervous system (CNS) myelination. Furthermore, we discuss myelin membrane trafficking with particular focus on endocytic recycling and the control of proteolipid protein (PLP) transport by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Finally, PLP mistrafficking is considered in the context of myelin diseases.
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Measurement bias detection through Bayesian factor analysis.
Front Psychol
PUBLISHED: 01-01-2014
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Measurement bias has been defined as a violation of measurement invariance. Potential violators-variables that possibly violate measurement invariance-can be investigated through restricted factor analysis (RFA). The purpose of the present paper is to investigate a Bayesian approach to estimate RFA models with interaction effects, in order to detect uniform and nonuniform measurement bias. Because modeling nonuniform bias requires an interaction term, it is more complicated than modeling uniform bias. The Bayesian approach seems especially suited for such complex models. In a simulation study we vary the type of bias (uniform, nonuniform), the type of violator (observed continuous, observed dichotomous, latent continuous), and the correlation between the trait and the violator (0.0, 0.5). For each condition, 100 sets of data are generated and analyzed. We examine the accuracy of the parameter estimates and the performance of two bias detection procedures, based on the DIC fit statistic, in Bayesian RFA. Results show that the accuracy of the estimated parameters is satisfactory. Bias detection rates are high in all conditions with an observed violator, and still satisfactory in all other conditions.
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Patients with single distal MCA perfusion lesions have a high rate of good outcome with or without reperfusion.
Int J Stroke
PUBLISHED: 12-23-2013
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Reperfusion is associated with good functional outcome after stroke. However, minimal data are available regarding the effect of reperfusion on clinical outcome and infarct growth in patients with distal MCA branch occlusions.
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Correlation of AOL recanalization, TIMI reperfusion and TICI reperfusion with infarct growth and clinical outcome.
J Neurointerv Surg
PUBLISHED: 12-18-2013
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To understand how three commonly used measures of endovascular therapy correlate with clinical outcome and infarct growth.
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A score based on age and DWI volume predicts poor outcome following endovascular treatment for acute ischemic stroke.
Int J Stroke
PUBLISHED: 11-12-2013
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The Houston Intra-Arterial Therapy score predicts poor functional outcome following endovascular treatment for acute ischemic stroke based on clinical variables. The present study sought to (a) create a predictive scoring system that included a neuroimaging variable and (b) determine if the scoring systems predict the clinical response to reperfusion.
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Pilot study of intravenous glyburide in patients with a large ischemic stroke.
Stroke
PUBLISHED: 11-05-2013
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Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. We assessed the feasibility of recruiting and treating patients with severe stroke while obtaining preliminary information on the safety and tolerability of RP-1127 (glyburide for injection).
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Stroke treatment academic industry roundtable: research priorities in the assessment of neurothrombectomy devices.
Stroke
PUBLISHED: 11-05-2013
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The goal of the Stroke Treatment Academic Industry Roundtable (STAIR) meetings is to advance the development of stroke therapies. At STAIR VIII, consensus recommendations were developed for clinical trial strategies to demonstrate the benefit of endovascular reperfusion therapies for acute ischemic stroke.
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Pathological T0 Following Radical Cystectomy with or without Neoadjuvant Chemotherapy: A Useful Surrogate.
J. Urol.
PUBLISHED: 10-14-2013
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Several large, randomized, controlled trials provide evidence that neoadjuvant chemotherapy improves the outcome of muscle invasive urothelial bladder cancer after radical cystectomy. We analyzed the designs, methods and observations of these trials to identify patient subgroups that appeared most likely to benefit. We also identified distinguishing features compared to groups that did not achieve improved outcomes.
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Radiological examinations of transient ischemic attack.
Front Neurol Neurosci
PUBLISHED: 10-11-2013
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Neuroimaging is critical in the evaluation of patients with TIA. CT and MRI are the two available options for imaging. Head CT is more widely available and commonly used. Diffusion MRI is the recommended modality to image an ischemic lesion. The presence of a diffusion lesion in a patient with transient neurological symptoms is an indicator of a high risk of recurrent stroke. Perfusion imaging with perfusion MRI or CT perfusion may improve the detection of ischemic lesions. Noninvasive vessel imaging may detect a symptomatic vessel lesion associated with an increased risk of stroke.
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THRIVE Score Predicts Outcomes With a Third-Generation Endovascular Stroke Treatment Device in the TREVO-2 Trial.
Stroke
PUBLISHED: 09-26-2013
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Several outcome prediction scores have been tested in patients receiving acute stroke treatment with previous generations of endovascular stroke treatment devices. The TREVO-2 trial was a randomized controlled trial comparing a novel endovascular stroke treatment device (the Trevo device) to a previous-generation endovascular stroke treatment device (the Merci device).
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Do MCI patients with vitamin B12 deficiency have distinctive cognitive deficits?
BMC Res Notes
PUBLISHED: 09-03-2013
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Vitamin B12 deficiency is common in older people, and may be responsible for reversible dementia. Low serum vitamin B12 levels were also observed in patients with Mild Cognitive Impairment (MCI). It is not known whether patients with vitamin B12 deficiency have a distinctive profile of cognitive impairment different from the episodic memory deficit usually observed in MCI.
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[Jugular vein thrombosis caused by hypercoagulability following in-vitro fertilization-activated protein C resistance and immobilization].
HNO
PUBLISHED: 08-31-2013
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Jugular vein thrombosis (JVT) is extremely difficult to diagnose clinically because of its rarity, the wide range of possible symptoms and the variety of differential diagnoses. A rapid diagnosis is important in order to avoid or prevent imminent life-threatening complications. This study reports a clinical case of extensive JVT due to increased thrombophilia in conjunction with ovarian hyperstimulation syndrome (OHSS) after in vitro fertilization, increased APC resistance and immobilization. It also discusses the current literature that forms the basis for recommendations regarding the diagnosis, therapy and interdisciplinary management.
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Six-Month Progression-Free Survival as the Primary Endpoint to Evaluate the Activity of New Agents as Second-line Therapy for Advanced Urothelial Carcinoma.
Clin Genitourin Cancer
PUBLISHED: 08-12-2013
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Second-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents.
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3-T in-bore MR-guided prostate biopsy based on a scoring system for target lesions characterization.
Acta Radiol
PUBLISHED: 07-22-2013
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To estimate potential malignant lesions within the prostate gland, the usage of a scoring system has recently been proposed by a European consensus meeting.
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[Acute physical exercise increases homocysteine concentrations in young trained male subjects].
Nutr Hosp
PUBLISHED: 07-05-2013
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High levels of homocysteine (Hcy) have been identified as a cardiovascular risk factor. Regarding physical exercise, the results are contradictory.
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Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication.
PLoS Biol.
PUBLISHED: 07-01-2013
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Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca²? entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.
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Imaging recommendations for acute stroke and transient ischemic attack patients: a joint statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery.
J Am Coll Radiol
PUBLISHED: 06-10-2013
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In the article entitled "Imaging Recommendations for Acute Stroke and Transient Ischemic Attack Patients: A Joint Statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery", we are proposing a simple, pragmatic approach that will allow the reader to develop an optimal imaging algorithm for stroke patients at their institution.
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Neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer: which patients benefit?
Eur. Urol.
PUBLISHED: 05-27-2013
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Level I evidence supports neoadjuvant chemotherapy in the treatment of advanced bladder cancer. For the most benefit, it is suggested that neoadjuvant chemotherapy be restricted to patients with clinical T3 disease and/or clinical N+ disease.
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Increased signal intensity of prostate lesions on high b-value diffusion-weighted images as a predictive sign of malignancy.
Eur Radiol
PUBLISHED: 05-22-2013
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The evaluation of lesions detected in prostate magnetic resonance imaging (MRI) with increased signal intensity (SI) on high b-value diffusion-weighted images as a sign of malignancy.
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ALDH1-positive cancer stem-like cells are enriched in nodal metastases of oropharyngeal squamous cell carcinoma independent of HPV status.
Oncol. Rep.
PUBLISHED: 03-11-2013
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Oropharyngeal squamous cell carcinoma (OSCC) is caused by high-risk (HR) human papillomavirus (HPV) or alcohol and tobacco abuse. Aldehyde dehydrogenase 1 (ALDH1) is a confirmed marker for cancer stem-like cells (CSCs) of OSCC responsible for therapy resistance, recurrence and metastasis. Associations between HR-HPV/p16, CSC frequency and clinicopathological parameters in patients with metastatic OSCC were investigated. In the present study, HPV genotypes and expression of ALDH1 and p16 was analyzed in 40 paired OSCC and metastases. A significant correlation between ALDH1 positivity with lower primary tumor differentiation grade (P=0.009) and higher nodal status (P=0.015) was noted. Compared to primary tumors, the proportion of ALDH1-expressing cells was significantly increased in metastases (P=0.012), while significantly fewer ALDH1-expressing cells were found in HR-HPV-DNA?/p16? primary tumors (P=0.038) compared to HR-HPV-DNA?/p16? primary tumors. Metastases showed no difference. ALDH1? CSCs are detectable in OSCC and metastases. ALDH1 high-grade OSCC exhibits a more aggressive phenotype characterized by higher nodal classification and lower differentiation. This suggests a subpopulation contained in the ALDH1-positive OSCC cell pool able to complete the metastatic cascade and subsequently enriching in metastasis independent of tumor etiology and ALDH1 content.
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Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice.
EMBO Mol Med
PUBLISHED: 03-08-2013
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The combinations of genetic alterations that cooperate with von Hippel-Lindau (VHL) mutation to cause clear cell renal cell carcinoma (ccRCC) remain poorly understood. We show that the TP53 tumour suppressor gene is mutated in approximately 9% of human ccRCCs. Combined deletion of Vhl and Trp53 in primary mouse embryo fibroblasts causes proliferative dysregulation and high rates of aneuploidy. Deletion of these genes in the epithelium of the kidney induces the formation of simple cysts, atypical cysts and neoplasms, and deletion in the epithelia of the genital urinary tract leads to dysplasia and tumour formation. Kidney cysts display a reduced frequency of primary cilia and atypical cysts and neoplasms exhibit a pro-proliferative signature including activation of mTORC1 and high expression of Myc, mimicking several cellular and molecular alterations seen in human ccRCC and its precursor lesions. As the majority of ccRCC is associated with functional inactivation of VHL, our findings suggest that for a subset of ccRCC, loss of p53 function represents a critical event in tumour development.
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Impaired bone formation and increased osteoclastogenesis in mice lacking chemokine (C-C motif) ligand 5 (Ccl5).
J. Bone Miner. Res.
PUBLISHED: 03-01-2013
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Chemokines play crucial roles in the recruitment of specific hematopoietic cell types, and some of them have been suggested to be involved in the regulation of bone remodeling. Because we have previously observed that chemokine (C-C motif) ligand 2 (Ccl2) and Ccl5 are direct target genes of noncanonical Wnt signaling in osteoblasts, we analyzed the skeletal phenotypes of Ccl2-deficient and Ccl5-deficient mice. In line with previous studies, Ccl2-deficient mice display a moderate reduction of osteoclastogenesis at the age of 6 months. In contrast, 6-month-old Ccl5-deficient mice display osteopenia associated with decreased bone formation and increased osteoclastogenesis. Moreover, unlike in wild-type and Ccl2-deficient mice, large areas of their trabecular and endocortical bone surfaces are not covered by osteoblasts or bone-lining cells, and this is associated with a severe reduction of endosteal bone formation. Although this phenotype diminishes with age, it is important that we could further identify a reduced number of osteal macrophages in 6-month-old Ccl5-deficient mice, because this cell type has previously been reported to promote endosteal bone formation. Because Ccl5-deficient mice also display increased osteoclastogenesis, we finally addressed the question of whether osteal macrophages could differentiate into osteoclasts and/or secrete inhibitors of osteoclastogenesis. For that purpose we isolated these cells by CD11b affinity purification from calvarial cultures and characterized them ex vivo. Here we found that they are unable to differentiate into osteoblasts or osteoclasts, but that their conditioned medium mediates an antiosteoclastogenic effect, possibly caused by interleukin-18 (IL-18), an inhibitor of osteoclastogenesis expressed by osteal macrophages. Taken together, our data provide in vivo evidence supporting the previously suggested role of Ccl5 in bone remodeling. Moreover, to the best of our knowledge, Ccl5-deficient mice represent the first model with a spontaneous partial deficiency of osteal macrophages, a recently identified cell type, whose impact on bone remodeling is just beginning to be understood.
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Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin.
J. Cell Biol.
PUBLISHED: 02-11-2013
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Although Wnt signaling is considered a key regulatory pathway for bone formation, inactivation of ?-catenin in osteoblasts does not affect their activity but rather causes increased osteoclastogenesis due to insufficient production of osteoprotegerin (Opg). By monitoring the expression pattern of all known genes encoding Wnt receptors in mouse tissues and bone cells we identified Frizzled 8 (Fzd8) as a candidate regulator of bone remodeling. Fzd8-deficient mice displayed osteopenia with normal bone formation and increased osteoclastogenesis, but this phenotype was not associated with impaired Wnt signaling or Opg production by osteoblasts. The deduced direct negative influence of canonical Wnt signaling on osteoclastogenesis was confirmed in vitro and through the generation of mice lacking ?-catenin in the osteoclast lineage. Here, we observed increased bone resorption despite normal Opg production and a resistance to the anti-osteoclastogenic effect of Wnt3a. These results demonstrate that Fzd8 and ?-catenin negatively regulate osteoclast differentiation independent of osteoblasts and that canonical Wnt signaling controls bone resorption by two different mechanisms.
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Femoroacetabular impingement predisposes to traumatic posterior hip dislocation.
Clin. Orthop. Relat. Res.
PUBLISHED: 02-07-2013
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Traumatic posterior hip dislocation in adults is generally understood to be the result of a high-energy trauma. Aside from reduced femoral antetorsion, morphologic risk factors for dislocation are unknown. We previously noticed that some hips with traumatic posterior dislocations had evidence of morphologic features of femoroacetabular impingement (FAI), therefore, we sought to evaluate that possibility more formally.
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CO? laser revision stapedotomy.
Laryngoscope
PUBLISHED: 01-31-2013
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To evaluate the safety and efficacy of the one-shot noncontact technique in stapedotomy for revision stapes surgery with a CO? laser combined with a scanning system.
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Impact of response to prior chemotherapy in patients with advanced urothelial carcinoma receiving second-line therapy: implications for trial design.
Clin Genitourin Cancer
PUBLISHED: 01-26-2013
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The prognostic impact of response to prior chemotherapy independent of performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) in the context of second-line therapy for advanced urothelial carcinoma (UC) is unknown.
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Physical strength is associated with Mini-Mental State Examination scores in Spanish institutionalized elderly.
Geriatr Gerontol Int
PUBLISHED: 01-22-2013
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The present cross-sectional study aimed at assessing muscle strength of hands, the dominant arm and legs in Spanish institutionalized elderly people according to sex, age and cognitive status.
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A critical role for the cholesterol-associated proteolipids PLP and M6B in myelination of the central nervous system.
Glia
PUBLISHED: 01-16-2013
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The formation of central nervous system myelin by oligodendrocytes requires sterol synthesis and is associated with a significant enrichment of cholesterol in the myelin membrane. However, it is unknown how oligodendrocytes concentrate cholesterol above the level found in nonmyelin membranes. Here, we demonstrate a critical role for proteolipids in cholesterol accumulation. Mice lacking the most abundant myelin protein, proteolipid protein (PLP), are fully myelinated, but PLP-deficient myelin exhibits a reduced cholesterol content. We therefore hypothesized that "high cholesterol" is not essential in the myelin sheath itself but is required for an earlier step of myelin biogenesis that is fully compensated for in the absence of PLP. We also found that a PLP-homolog, glycoprotein M6B, is a myelin component of low abundance. By targeting the Gpm6b-gene and crossbreeding, we found that single-mutant mice lacking either PLP or M6B are fully myelinated, while double mutants remain severely hypomyelinated, with enhanced neurodegeneration and premature death. As both PLP and M6B bind membrane cholesterol and associate with the same cholesterol-rich oligodendroglial membrane microdomains, we suggest a model in which proteolipids facilitate myelination by sequestering cholesterol. While either proteolipid can maintain a threshold level of cholesterol in the secretory pathway that allows myelin biogenesis, lack of both proteolipids results in a severe molecular imbalance of prospective myelin membrane. However, M6B is not efficiently sorted into mature myelin, in which it is 200-fold less abundant than PLP. Thus, only PLP contributes to the high cholesterol content of myelin by association and co-transport.
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Impingement adversely affects 10-year survivorship after periacetabular osteotomy for DDH.
Clin. Orthop. Relat. Res.
PUBLISHED: 01-08-2013
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Although periacetabular osteotomy (PAO) for developmental dysplasia of the hip (DDH) provides conceptual advantages compared with other osteotomies and reportedly is associated with joint survivorship of 60% at 20 years, the beneficial effect of proper acetabular reorientation with concomitant arthrotomy and creation of femoral head-neck offset on 10-year hip survivorship remains unclear.
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Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer.
Invest New Drugs
PUBLISHED: 01-06-2013
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AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (Cmax) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609).
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Extracellular vesicles as mediators of neuron-glia communication.
Front Cell Neurosci
PUBLISHED: 01-01-2013
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In the nervous system, glia cells maintain homeostasis, synthesize myelin, provide metabolic support, and participate in immune defense. The communication between glia and neurons is essential to synchronize these diverse functions with brain activity. Evidence is accumulating that secreted extracellular vesicles (EVs), such as exosomes and shedding microvesicles, are key players in intercellular signaling. The cells of the nervous system secrete EVs, which potentially carry protein and RNA cargo from one cell to another. After delivery, the cargo has the ability to modify the target cell phenotype. Here, we review the recent advances in understanding the role of EV secretion by astrocytes, microglia, and oligodendrocytes in the central nervous system. Current work has demonstrated that oligodendrocytes transfer exosomes to neurons as a result of neurotransmitter signaling suggesting that these vesicles may mediate glial support of neurons.
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Glial promoter selectivity following AAV-delivery to the immature brain.
PLoS ONE
PUBLISHED: 01-01-2013
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Recombinant adeno-associated virus (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in adult rodents have shown that the use of cell type-specific promoters is sufficient to target AAV-mediated transgene expression to glia. However, neurological disorders caused by glial pathology usually have an early onset. Therefore, modelling and treatment of these conditions require expanding the concept of targeted glial transgene expression by promoter selectivity for gene delivery to the immature CNS. Here, we have investigated the AAV-mediated green fluorescent protein (GFP) expression driven by the myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP) promoters in the developing mouse brain. Generally, the extent of transgene expression after infusion at immature stages was widespread and higher than in adults. The GFAP promoter-driven GFP expression was found to be highly specific for astrocytes following vector infusion to the brain of neonates and adults. In contrast, the selectivity of the MBP promoter for oligodendrocytes was poor following neonatal AAV delivery, but excellent after vector injection at postnatal day 10. To extend these findings obtained in naïve mice to a disease model, we performed P10 infusions of AAV-MBP-GFP in aspartoacylase (ASPA)-deficient mouse mutants presenting with early onset oligodendrocyte pathology. Spread of GFP expression and selectivity for oligodendrocytes in ASPA-mutants was comparable with our observations in normal animals. Our data suggest that direct AAV infusion to the developing postnatal brain, utilising cellular promoters, results in targeted and long-term transgene expression in glia. This approach will be relevant for disease modelling and gene therapy for the treatment of glial pathology.
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Heterogeneous nuclear ribonucleoprotein (hnRNP) F is a novel component of oligodendroglial RNA transport granules contributing to regulation of myelin basic protein (MBP) synthesis.
J. Biol. Chem.
PUBLISHED: 11-29-2011
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Myelin basic protein (MBP) is a major component of central nervous system (CNS) myelin. The absence of MBP results in the loss of almost all compact myelin in the CNS. MBP mRNA is sorted into RNA granules that are transported to the periphery of oligodendrocytes in a translationally inactive state. A central mediator of this transport process is the trans-acting factor heterogeneous nuclear ribonucleoprotein (hnRNP) A2 that binds to the cis-acting A2-response element in the 3UTR of MBP mRNA. Recently, we found that activation of the Src family nonreceptor tyrosine kinase Fyn in oligodendrocytes leads to phosphorylation of hnRNP A2 and to increased translation of MBP mRNA. Here, we identify the RNA-binding protein hnRNP F as a novel component of MBP mRNA transport granules. It is associated with hnRNP A2 and MBP mRNA in cytoplasmic granular structures and is involved in post-transcriptional regulation of MBP expression. Fyn kinase activity results in phosphorylation of hnRNP F in the cytoplasm and its release from MBP mRNA and RNA granules. Our results define hnRNP F as a regulatory element of MBP expression in oligodendrocytes and imply an important function of hnRNP F in the control of myelin synthesis.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.