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Find video protocols related to scientific articles indexed in Pubmed.
Pyocyanin inhibits both nitric oxide-dependent and independent relaxation in porcine coronary arteries.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 11-18-2014
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The effects of the Pseudomonas aeruginosa virulence factor pyocyanin (PCN) on contractile function of porcine coronary arteries was investigated in vitro. Artery rings (5 mm) were suspended in organ baths containing Krebs solution for the measurement of isometric tension. The effect of PCN on resting and precontracted coronary arteries was initially investigated with various agents. Arteries were precontracted with prostaglandin F2? or potassium chloride, and endothelium-dependent relaxations were induced by various agents in the presence of PCN. PCN evoked small amplitude dose-dependent contractions in resting porcine coronary arteries. PCN also amplified the contractile response to prostaglandin F2?, but did not alter responses to carbachol. PCN (0.1-10 ?M) significantly inhibited endothelium-dependent relaxations evoked by neurokinin A. PCN also inhibited relaxations evoked by diethylamine nitric oxide (nitric oxide donor), forskolin (adenylate cyclase activator), dibuytyryl-cAMP (cAMP analog), 8-bromo-cGMP (cGMP analog) and P1075 (KATP channel activator), but not isoprenaline (?-adrenoceceptor agonist). These results indicate that physiological concentrations of PCN interfere with multiple intracellular processes involved in vascular smooth muscle relaxation, in particular pathways downstream of nitric oxide release. Thus PCN may alter normal vascular function in patients infected with P. aeruginosa. This article is protected by copyright. All rights reserved.
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Wnt/?-catenin and FGF signalling direct the specification and maintenance of a neuromesodermal axial progenitor in ensembles of mouse embryonic stem cells.
Development
PUBLISHED: 11-06-2014
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The development of the central nervous system is known to result from two sequential events. First, an inductive event of the mesoderm on the overlying ectoderm that generates a neural plate that, after rolling into a neural tube, acts as the main source of neural progenitors. Second, the axial regionalization of the neural plate that will result in the specification of neurons with different anteroposterior identities. Although this description of the process applies with ease to amphibians and fish, it is more difficult to confirm in amniote embryos. Here, a specialized population of cells emerges at the end of gastrulation that, under the influence of Wnt and FGF signalling, expands and generates the spinal cord and the paraxial mesoderm. This population is known as the long-term neuromesodermal precursor (NMp). Here, we show that controlled increases of Wnt/?-catenin and FGF signalling during adherent culture differentiation of mouse embryonic stem cells (mESCs) generates a population with many of the properties of the NMp. A single-cell analysis of gene expression within this population reveals signatures that are characteristic of stem cell populations. Furthermore, when this activation is triggered in three-dimensional aggregates of mESCs, the population self-organizes macroscopically and undergoes growth and axial elongation that mimics some of the features of the embryonic spinal cord and paraxial mesoderm. We use both adherent and three-dimensional cultures of mESCs to probe the establishment and maintenance of NMps and their differentiation.
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Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells.
Development
PUBLISHED: 11-06-2014
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Mouse embryonic stem cells (mESCs) are clonal populations derived from preimplantation mouse embryos that can be propagated in vitro and, when placed into blastocysts, contribute to all tissues of the embryo and integrate into the normal morphogenetic processes, i.e. they are pluripotent. However, although they can be steered to differentiate in vitro into all cell types of the organism, they cannot organise themselves into structures that resemble embryos. When aggregated into embryoid bodies they develop disorganised masses of different cell types with little spatial coherence. An exception to this rule is the emergence of retinas and anterior cortex-like structures under minimal culture conditions. These structures emerge from the cultures without any axial organisation. Here, we report that small aggregates of mESCs, of about 300 cells, self-organise into polarised structures that exhibit collective behaviours reminiscent of those that cells exhibit in early mouse embryos, including symmetry breaking, axial organisation, germ layer specification and cell behaviour, as well as axis elongation. The responses are signal specific and uncouple processes that in the embryo are tightly associated, such as specification of the anteroposterior axis and anterior neural development, or endoderm specification and axial elongation. We discuss the meaning and implications of these observations and the potential uses of these structures which, because of their behaviour, we suggest to call 'gastruloids'.
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Comparison of whole-body vibration exposures in buses: effects and interactions of bus and seat design.
Ergonomics
PUBLISHED: 10-08-2014
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Bus and seat design may be important for the drivers' whole-body vibration (WBV). WBV exposures in buses during actual operation were assessed. WBV attenuation performance between an air-suspension seat and a static pedestal seat in low-floor buses was compared; there were no differences in WBV attenuation between the seats. Air-suspension seat performance in a high-floor and low-floor bus was compared. Relative to the pedestal seat with its relatively static, limited travel seat suspension, the air-suspension seat with its dynamic, longer travel suspension provided little additional benefit. Relative to the measurement collected at the bus floor, the air-suspension seat amplified the WBV exposures in the high-floor bus. All WBV exposures were below European Union (EU) daily exposure action values. The EU Vibration Directive only allows the predominant axis of vibration exposure to be evaluated but a tri-axial vector sum exposure may be more representative of the actual health risks.
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Prediction of trapezius muscle activity and shoulder, head, neck, and torso postures during computer use: results of a field study.
BMC Musculoskelet Disord
PUBLISHED: 09-03-2014
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Due to difficulties in performing direct measurements as an exposure assessment technique, evidence supporting an association between physical exposures such as neck and shoulder muscle activities and postures and musculoskeletal disorders during computer use is limited. Alternative exposure assessment techniques are needed.
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Pseudohyperphosphatemia in children treated with liposomal amphotericin B.
Am J Health Syst Pharm
PUBLISHED: 08-23-2014
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The results of a study to determine the frequency of pseudohyperphosphatemia in a sample of pediatric patients treated with i.v. liposomal amphotericin B are reported.
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Fatigue development in the finger flexor muscle differs between keyboard and mouse use.
Eur. J. Appl. Physiol.
PUBLISHED: 08-09-2014
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The aim of the present study was to determine whether there were any physiological changes in the muscle as a result of intensive computer use.
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Fc? receptor dependency of agonistic CD40 antibody in lymphoma therapy can be overcome through antibody multimerization.
J. Immunol.
PUBLISHED: 07-14-2014
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Immunomodulatory mAbs, led by the anti-CTLA4 mAb ipilimumab, are an exciting new class of drugs capable of promoting anticancer immunity and providing durable control of some tumors. Close analysis of a number of agents has revealed a critical yet variable role for Fc? receptors in their efficacy. In this article, we reveal that agonistic anti-CD40 mAbs have an absolute requirement for cross-linking by inhibitory Fc?RIIB when used systemically to treat established BCL1 syngeneic lymphoma, and therapy is lost when using a mouse IgG2a mAb not cross-linked by Fc?RIIB. Furthermore, in Fc?RIIB-deficient mice the lymphoma itself can provide Fc?RIIB to cross-link anti-CD40 on neighboring cells, and only when this is blocked does therapy fail. The dependence on Fc?RIIB for immunostimulatory activity was not absolute, however, because when anti-CD40 mAbs were administered systemically with the TLR3 agonist polyinosinic:polycytidylic acid or were given subcutaneously, activatory Fc?R could also provide cross-linking. Using this mechanistic insight, we designed multimeric forms of anti-CD40 mAb with intrinsic Fc?R-independent activity that were highly effective in the treatment of lymphoma-bearing mice. In conclusion, Fc?R-independent anti-CD40 activation is a viable strategy in vivo. These findings have important translational implications, as humans, unlike mice, do not have IgG that binds strongly to Fc?RIIB; therefore Fc?R-independent derivatives represent an attractive therapeutic option.
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Molecular mechanism of ligand recognition by membrane transport protein, Mhp1.
EMBO J.
PUBLISHED: 06-21-2014
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The hydantoin transporter Mhp1 is a sodium-coupled secondary active transport protein of the nucleobase-cation-symport family and a member of the widespread 5-helix inverted repeat superfamily of transporters. The structure of Mhp1 was previously solved in three different conformations providing insight into the molecular basis of the alternating access mechanism. Here, we elucidate detailed events of substrate binding, through a combination of crystallography, molecular dynamics, site-directed mutagenesis, biochemical/biophysical assays, and the design and synthesis of novel ligands. We show precisely where 5-substituted hydantoin substrates bind in an extended configuration at the interface of the bundle and hash domains. They are recognised through hydrogen bonds to the hydantoin moiety and the complementarity of the 5-substituent for a hydrophobic pocket in the protein. Furthermore, we describe a novel structure of an intermediate state of the protein with the external thin gate locked open by an inhibitor, 5-(2-naphthylmethyl)-L-hydantoin, which becomes a substrate when leucine 363 is changed to an alanine. We deduce the molecular events that underlie acquisition and transport of a ligand by Mhp1.
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Use of continuous-infusion loop diuretics in critically ill children.
Pharmacotherapy
PUBLISHED: 06-05-2014
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Loop diuretics are commonly used in critically ill children to achieve appropriate fluid balance. They are often administered as a continuous intravenous infusion (CI) in hemodynamically unstable children because of fewer alterations in central venous pressure, oxygen saturation, and heart rate compared with scheduled intermittent dosing. During the past few years, however, drug shortages have been reported for bumetanide, torsemide, and furosemide. Therefore, to explore the use of alternative agents for CI, we performed a literature search to identify articles evaluating the use of furosemide, bumetanide, ethacrynic acid, and torsemide CI in critically ill children. The search was limited to English-language articles in the MEDLINE (1946-December 2013), EMBASE (1980-December 2013), and International Pharmaceutical Abstracts (1970-December 2013) databases and the Cochrane Database of Systematic Reviews (2005-December 2013). Reference citations from relevant articles were also reviewed. A total of 10 reports representing 173 pediatric patients were included in the analysis. Most of the reports provided evidence for furosemide, and no reports with torsemide were identified. Wide variability in CI dosing was reported in these studies. When selecting the loop diuretic CI for critically ill patients, clinicians should consider their adverse-event profiles, compatibility with other concomitant intravenous infusions, and pharmacoeconomics. Fluid balance and urine output should be monitored routinely to ensure appropriate response. The lowest initial dose should be used to achieve an appropriate fluid balance and target urine output of 1-3 ml/kg/hour while limiting the likelihood of toxicity.
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Neuroblastoma in a 17-week fetus: A stimulus for investigation of tumors in a series of 2786 stillbirth and late miscarriages.
Am. J. Med. Genet. A
PUBLISHED: 05-28-2014
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Although tumors are an occasional cause of neonatal death and have been reported in stillbirths, there are no studies specifically evaluating the frequency or types of tumors in stillborn infants. We observed metastatic neuroblastoma in a fetus miscarried at 17 weeks of gestational age. Fetal death was attributed to endocrine effects of the tumor causing fetal hypertension, arrhythmia, and/or placental dysfunction. This case, which is the earliest report of a pathologically confirmed neuroblastoma, prompted review of all tumors in the Wisconsin Stillbirth Service Program database. There were 10 lethal and two incidental tumors among the 2,786 stillbirths and second trimester miscarriages in the database for an overall incidence of 1/232, which is about 50 times the incidence of clinically recognized tumors in liveborn infants. The most frequent tumors were teratoma and hemangioma that, while benign, caused death due to high output cardiac failure, hemorrhage into the tumor, or obstruction of vital organs. Only three tumors were malignant, and except for the index case, mechanisms of death were similar to those of the benign tumors. Except for the index case, all were found in the third trimester, suggesting that congenital tumors rarely become lethal until the third trimester. However, it is also possible that tumors may be missed in younger fetuses. The possibility of detecting an unsuspected tumor is yet another reason for autopsy in stillbirths and late miscarriages. © 2014 Wiley Periodicals, Inc.
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Office workers with high effort-reward imbalance and overcommitment have greater decreases in heart rate variability over a 2-h working period.
Int Arch Occup Environ Health
PUBLISHED: 05-23-2014
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High levels of workplace psychosocial factors have been associated with adverse cardiovascular outcomes, possibly through the pathway of increasing autonomic arousal. The purpose of this study was to investigate whether the workplace psychosocial factors of effort-reward imbalance (ERI) and overcommitment were associated with greater decreases in heart rate variability (HRV) across a 2-h working period in a cohort of office workers performing their own work at their own workplaces.
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Differential impact of CD27 and 4-1BB costimulation on effector and memory CD8 T cell generation following peptide immunization.
J. Immunol.
PUBLISHED: 05-23-2014
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The factors that determine differentiation of naive CD8 T cells into memory cells are not well understood. A greater understanding of how memory cells are generated will inform of ways to improve vaccination strategies. In this study, we analyzed the CD8 T cell response elicited by two experimental vaccines comprising a peptide/protein Ag and an agonist that delivers a costimulatory signal via CD27 or 4-1BB. Both agonists increased expansion of Ag-specific CD8 T cells compared with Ag alone. However, their capacity to stimulate differentiation into effector and memory cells differed. CD27 agonists promoted increased expression of perforin and the generation of short-lived memory cells, whereas stimulation with 4-1BB agonists favored generation of stable memory. The memory-promoting effects of 4-1BB were independent of CD4 T cells and were the result of programing within the first 2 d of priming. Consistent with this conclusion, CD27 and 4-1BB-stimulated CD8 T cells expressed disparate amounts of IL-2, IFN-?, CD25, CD71, and Gp49b as early as 3 d after in vivo activation. In addition, memory CD8 T cells, generated through priming with CD27 agonists, proliferated more extensively than did 4-1BB-generated memory cells, but these cells failed to persist. These data demonstrate a previously unanticipated link between the rates of homeostatic proliferation and memory cell attrition. Our study highlights a role for these receptors in skewing CD8 T cell differentiation into effector and memory cells and provides an approach to optimize vaccines that elicit CD8 T cell responses.
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Ethacrynic Acid continuous infusions in critically ill pediatric patients.
J Pediatr Pharmacol Ther
PUBLISHED: 05-01-2014
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The purpose of this study was to describe dosage regimens and treatment outcomes in critically ill children receiving ethacrynic acid continuous infusions (CI).
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Office workers' computer use patterns are associated with workplace stressors.
Appl Ergon
PUBLISHED: 04-09-2014
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This field study examined associations between workplace stressors and office workers' computer use patterns. We collected keyboard and mouse activities of 93 office workers (68F, 25M) for approximately two work weeks. Linear regression analyses examined the associations between self-reported effort, reward, overcommitment, and perceived stress and software-recorded computer use duration, number of short and long computer breaks, and pace of input device usage. Daily duration of computer use was, on average, 30 min longer for workers with high compared to low levels of overcommitment and perceived stress. The number of short computer breaks (30 s-5 min long) was approximately 20% lower for those with high compared to low effort and for those with low compared to high reward. These outcomes support the hypothesis that office workers' computer use patterns vary across individuals with different levels of workplace stressors.
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Antimicrobial activity of a novel adhesive containing chlorhexidine gluconate (CHG) against the resident microflora in human volunteers.
J. Antimicrob. Chemother.
PUBLISHED: 04-09-2014
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To evaluate the antimicrobial activity of a new, transparent composite film dressing, whose adhesive contains chlorhexidine gluconate (CHG), against the native microflora present on human skin.
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Differences in typing forces, muscle activity, comfort, and typing performance among virtual, notebook, and desktop keyboards.
Appl Ergon
PUBLISHED: 03-27-2014
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The present study investigated whether there were physical exposure and typing productivity differences between a virtual keyboard with no tactile feedback and two conventional keyboards where key travel and tactile feedback are provided by mechanical switches under the keys. The key size and layout were same across all the keyboards. Typing forces; finger and shoulder muscle activity; self-reported comfort; and typing productivity were measured from 19 subjects while typing on a virtual (0 mm key travel), notebook (1.8 mm key travel), and desktop keyboard (4 mm key travel). When typing on the virtual keyboard, subjects typed with less force (p's < 0.0001) and had lower finger flexor/extensor muscle activity (p's < 0.05). However, the lower typing forces and finger muscle activity came at the expense of a 60% reduction in typing productivity (p < 0.0001), decreased self-reported comfort (p's < 0.0001), and a trend indicating an increase in shoulder muscle activity (p's < 0.10). Therefore, for long typing sessions or when typing productivity is at a premium, conventional keyboards with tactile feedback may be more suitable interface.
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Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness.
Nat. Chem. Biol.
PUBLISHED: 03-27-2014
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cAMP mediates autonomic regulation of heart rate by means of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current If. cAMP binding to the C-terminal cyclic nucleotide binding domain enhances HCN open probability through a conformational change that reaches the pore via the C-linker. Using structural and functional analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic dinucleotides, an emerging class of second messengers in mammals, bind the C-linker pocket (CLP) and antagonize cAMP regulation of the channel. Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder ?-adrenergic stimulation on If. Our results highlight the regulative role of the C-linker and identify a potential drug target in HCN4. Furthermore, these data extend the signaling scope of cyclic dinucleotides in mammals beyond their first reported role in innate immune system.
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Awareness of the role of science in the FDA regulatory submission process: a survey of the TERMIS-Americas membership.
Tissue Eng Part A
PUBLISHED: 03-27-2014
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The Industry Committee of the Tissue Engineering Regenerative Medicine International Society, Americas Chapter (TERMIS-AM) administered a survey to its membership in 2013 to assess the awareness of science requirements in the U.S. Food and Drug Administration (FDA) regulatory process. One hundred forty-four members responded to the survey. Their occupational and geographical representation was representative of the TERMIS-AM membership as a whole. The survey elicited basic demographic information, the degree to which members were involved in tissue engineering technology development, and their plans for future involvement in such development. The survey then assessed the awareness of general FDA scientific practices as well as specific science requirements for regulatory submissions to the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), the Center for Devices and Radiological Health (CDRH), and the Office of Combination Projects (OCP). The FDA-specific questions in the survey were culled from guidance documents posted on the FDA web site ( www.fda.gov ). One of the answer options was an opt-out clause that enabled survey respondents to claim a lack of sufficient awareness of the topic to answer the question. This enabled the stratification of respondents on the basis of confidence in the topic. Results indicate that across all occupational groups (academic, business, and government) that are represented in the TERMIS-AM membership, the awareness of FDA science requirements varies markedly. Those who performed best were for-profit company employees, consultants, and government employees; while students, professors, and respondents from outside the USA performed least well. Confidence in question topics was associated with increased correctness in responses across all groups, though the association between confidence and the ability to answer correctly was poorest among students and professors. Though 80% of respondents claimed involvement in the development of a tissue engineering technology, their responses were no more correct than those who were not. Among those developing tissue engineering technologies, few are taking advantage of existing standards organizations to strengthen their regulatory submissions. The data suggest that early exposure to regulatory experts would be of value for those seeking to bring their technology to the market. For all groups studied but especially for students and professors, formal initial or continuing education in Regulatory Science should be considered to best support translational tissue engineering research and development. In addition, the involvement of standards development organizations during tissue engineering technology development is strongly recommended.
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Competency-based training "Helping Mothers Survive: Bleeding after Birth" for providers from central and remote facilities in three countries.
Int J Gynaecol Obstet
PUBLISHED: 02-19-2014
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To validate a new training module for skilled and semiskilled birth attendants authorized to provide care at birth-Helping Mothers Survive: Bleeding After Birth (HMS:BAB)-aimed at reducing postpartum hemorrhage, the leading cause of maternal mortality worldwide. BAB training involves single-day, facility-based training that emphasizes simulation of scenarios related to prevention, detection, and management of postpartum hemorrhage.
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Variance of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) concentrations in activated, concentrated platelets from healthy male donors.
J Orthop Surg Res
PUBLISHED: 02-09-2014
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The use of autologous blood concentrates, such as activated, concentrated platelets, in orthopaedic clinical applications has had mixed results. Research on this topic has focused on growth factors and cytokines, with little directed towards matrix metalloproteinases (MMPs) which are involved in post-wound tissue remodeling.
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A case of neurosarcoidosis with labyrinthine involvement.
Case Rep Radiol
PUBLISHED: 02-03-2014
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Sarcoidosis is a chronic granulomatous disease of unknown aetiology, which may involve any organ system. It most commonly occurs in adults with childhood involvement being rare. Central nervous system involvement is seen in up to 25% and typically involves meningeal disease resulting in multiple cranial neuropathies. Other common clinical findings include seizures, headache, dementia, and pituitary dysfunction. Imaging plays a central role in the diagnosis with typical findings including pachymeningeal and leptomeningeal enhancing lesions. Other imaging findings include lacunar and major territory infarcts, hypothalamic and infundibular thickening, hydrocephalus, and cranial nerve enhancement. We present a case of an eight-year-old male patient with progressive headache, visual disturbance, unilateral sensory hearing loss, and multiple cranial neuropathies. Imaging findings demonstrated the classic pachymeningeal and leptomeningeal enhancement along much of the skull base, as well as enhancement of the right and left second and eighth cranial nerves. Extensive inflammatory changes were noted in the temporal bones and paranasal sinuses. There was also enhancement of the right and left labyrinths. Sinus biopsy confirmed sarcoidosis. We present the first case to our knowledge of sarcoid labyrinthitis.
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Noninvasive quantification of solid tumor microstructure using VERDICT MRI.
Cancer Res.
PUBLISHED: 02-03-2014
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There is a need for biomarkers that are useful for noninvasive imaging of tumor pathophysiology and drug efficacy. Through its use of endogenous water, diffusion-weighted MRI (DW-MRI) can be used to probe local tissue architecture and structure. However, most DW-MRI studies of cancer tissues have relied on simplistic mathematical models, such as apparent diffusion coefficient (ADC) or intravoxel incoherent motion (IVIM) models, which produce equivocal results on the relation of the model parameter estimate with the underlying tissue microstructure. Here, we present a novel technique called VERDICT (Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors) to quantify and map histologic features of tumors in vivo. VERDICT couples DW-MRI to a mathematical model of tumor tissue to access features such as cell size, vascular volume fraction, intra- and extracellular volume fractions, and pseudo-diffusivity associated with blood flow. To illustrate VERDICT, we used two tumor xenograft models of colorectal cancer with different cellular and vascular phenotypes. Our experiments visualized known differences in the tissue microstructure of each model and the significant decrease in cell volume resulting from administration of the cytotoxic drug gemcitabine, reflecting the apoptotic volume decrease. In contrast, the standard ADC and IVIM models failed to detect either of these differences. Our results illustrate the superior features of VERDICT for cancer imaging, establishing it as a noninvasive method to monitor and stratify treatment responses.
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Structural insights into interactions of C/EBP transcriptional activators with the Taz2 domain of p300.
Acta Crystallogr. D Biol. Crystallogr.
PUBLISHED: 01-29-2014
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Members of the C/EBP family of transcription factors bind to the Taz2 domain of p300/CBP and mediate its phosphorylation through the recruitment of specific kinases. Short sequence motifs termed homology boxes A and B, which comprise their minimal transactivation domains (TADs), are conserved between C/EBP activators and are necessary for specific p300/CBP binding. A possible mode of interaction between C/EBP TADs and the p300 Taz2 domain was implied by the crystal structure of a chimeric protein composed of residues 1723-1818 of p300 Taz2 and residues 37-61 of C/EBP?. The segment corresponding to the C/EBP? TAD forms two orthogonally disposed helices connected by a short linker and interacts with the core structure of Taz2 from a symmetry-related molecule. It is proposed that other members of the C/EBP family interact with the Taz2 domain in the same manner. The position of the C/EBP? peptide on the Taz2 protein interaction surface suggests that the N-termini of C/EBP proteins are unbound in the C/EBP-p300 Taz2 complex. This observation is in agreement with the known location of the docking site of protein kinase HIPK2 in the C/EBP? N-terminus, which associates with the C/EBP?-p300 complex.
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Neurodegeneration with brain iron accumulation in an eleven-year-old jamaican male.
Case Rep Radiol
PUBLISHED: 01-28-2014
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We present a case of an eleven-year-old boy presenting with progressive extrapyramidal signs and dementia. His imaging findings demonstrated the classic eye-of-the-tiger sign on T2W magnetic resonance imaging. He was diagnosed with pantothenate kinase-associated neurodegeneration (PKAN). This is a rare autosomal recessive inborn error of coenzyme A metabolism, caused by mutations in PANK2. This is the first reported case of PKAN from the Caribbean.
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Overcoming obstacles to establish a multidisciplinary team approach to hepatobiliary diseases: a working model in a Caribbean setting.
J Multidiscip Healthc
PUBLISHED: 01-01-2014
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By providing a structured forum to exchange information and ideas, multidisciplinary team meetings improve working relationships, expedite investigations, promote evidence-based treatment, and ultimately improve clinical outcomes.
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Spectrum of Echocardiographic Abnormalities among 168 Consecutive Referrals to an Urban Private Hospital in South-Western Nigeria.
Clin Med Insights Cardiol
PUBLISHED: 01-01-2014
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Trans-thoracic echocardiography (TTE) is an important non-invasive cardiac examination that provides structural and functional information. It is useful in the diagnosis of cardiac diseases and often guides the management and follow-up of patients with cardiovascular diseases (CVD). The study aimed to present an audit of the echocardiograms performed in an urban private hospital over a two-year period in order to define the pattern of cardiac diseases in our center. Echocardiogram reports of 168 consecutive patients performed between May 2011 and April 2013 at an organized private sector hospital in Lagos, south-west Nigeria were reviewed. Studies were performed with a Toshiba Nemio XG ultrasound machine. The data obtained were analyzed for mean age, sex, clinical indications, and echocardiographic diagnosis in the study subjects. A total of 168 echocardiography reports were examined, comprising of 92 males (54.8%) and 76 females (45.2%). The age range of the subjects was 10-76 years (mean 42.5 ± 12.1 years). The commonest indication for echocardiography was systemic hypertension and hypertension related causes (38.1%), followed by abnormal resting electrocardiogram (14.9%). Routine annual medical screening was the next most common indication, representing 13.1% of the indications for echocardiography. The other indications are as presented in Table 1. The echocardiogram was normal in 64.3% of the subjects. The commonest abnormality detected was hypertensive heart disease (HHD); accounting for 9.6% of the subjects studied. Isolated atrial enlargement (left, right, or bi-atrial) was the next most common abnormality accounting for 6% of the echocardiographic diagnosis. Pulmonary hypertension was the next most common diagnosis accounting for 4.8% of our findings. The other echocardiographic diagnoses are as listed in Table 2. Hypertension represents the commonest indication for echocardiography. Normal echocardiogram was the commonest echocardiographic finding while HHD was the commonest echocardiographic abnormality. The prevalence of ischemic heart disease by echocardiography was 2.4%. There was no case of rheumatic heart disease (RHD). The prevalence of hypertrophic cardiomyopathy (HCM) was 1.2%. Ease of access to echocardiography may influence the findings in an echocardiographic audit and policy makers should incorporate appropriateness criteria into their guidelines for reimbursement.
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Leadership in surgery for public sector hospitals in Jamaica: strategies for the operating room.
Perm J
PUBLISHED: 12-21-2013
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The barriers to health care delivery in developing nations are many: underfunding, limited support services, scarce resources, suboptimal health care worker attitudes, and deficient health care policies are some of the challenges. The literature contains little information about health care leadership in developing nations. This discursive paper examines the impact of leadership on the delivery of operating room (OR) services in public sector hospitals in Jamaica.Delivery of OR services in Jamaica is hindered by many unique cultural, financial, political, and environmental barriers. We identify six leadership goals adapted to this environment to achieve change.Effective leadership must adapt to the environment. Delivery of OR services in Jamaica may be improved by addressing leadership training, workplace safety, interpersonal communication, and work environment and by revising existing policies. Additionally, there should be regular practice audits and quality control surveys.
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Management of early-stage Hodgkin lymphoma: is there still a role for radiation?
Hematology Am Soc Hematol Educ Program
PUBLISHED: 12-10-2013
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Although radiotherapy is highly effective for the treatment of Hodgkin lymphoma, the realization of its potential long-term toxicity and the demonstration of excellent results from combination chemotherapy have led to a retreat from its use in early-stage disease. Recent trials using functional imaging may allow better identification of those patients for whom radiotherapy may be safely omitted without compromising cure rates and this review examines the evidence for this.
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Breaking bad news in clinical setting - health professionals experience and perceived competence in southwestern Nigeria: A cross sectional study.
Ann Afr Med
PUBLISHED: 12-07-2013
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Background: Communication skills are vital in clinical settings because the manner in which bad news is delivered could be a huge determinant of responses to such news; as well as compliance with beneficial treatment option. Information on training, institutional guidelines and protocols for breaking bad news (BBN) is scarce in Nigeria. We assessed the training, experience and perceived competence of BBN among medical personnel in southwestern Nigeria. Materials and Methods: The study was a cross-sectional descriptive study conducted out among doctors and nurses in two healthcare institutions in southwestern Nigeria using an anonymous questionnaire (adapted from the survey by Horwitz et al.), which focused on the respondents training, awareness of protocols in BBN; and perceived competence (using a Five-Point Likert Scale) in five clinical scenarios. We equally asked the respondents about an instance of BBN they have recently witnessed. Results: A total of 113 of 130 selected (response rate 86.9%) respondents were studied. Eight (7.1%) of the respondents knew of the guidelines on BBN in the hospital in which they work. Twenty-three (20.3%) respondents claimed knowledge of a protocol. The median perceived competence rating was 4 out of 5 in all the clinical scenarios. Twenty-five (22.1%) respondents have had a formal training in BBN and they generally had significant higher perceived competence rating (P = 0.003-0.021). There is poor support from fellow workers during instances of BBN. Conclusion: It appears that the large proportion of the respondents in this study were unconsciously incompetent in BBN in view of the low level of training and little or no knowledge of well known protocols for BBN even though self-rated competence is high. Continuous medical education in communication skills among health personnel in Nigeria is advocated.
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Association of Fentanyl With Neurodevelopmental Outcomes in Very-Low-Birth-Weight Infants.
Ann Pharmacother
PUBLISHED: 12-05-2013
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Opioids are commonly used in the neonatal intensive care unit (NICU). Negative neurodevelopmental effects in the short-term setting have been associated with opioids ; however, long-term studies have been limited.
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Acetazolamide in critically ill neonates and children with metabolic alkalosis.
Ann Pharmacother
PUBLISHED: 11-22-2013
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Acetazolamide is an option for hypochloremic metabolic alkalosis, but there are limited reports in children.
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External Validation of the Medication Taper Complexity Score for Methadone Tapers in Children With Opioid Abstinence Syndrome.
Ann Pharmacother
PUBLISHED: 11-12-2013
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Methadone is commonly prescribed for children with opioid abstinence syndrome (OAS) as a taper schedule over several days to weeks. The Medication Taper Complexity Score (MTCS) was developed to evaluate outpatient methadone tapers.
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De Novo Treatment of Diffuse Large B-Cell Lymphoma With Rituximab, Cyclophosphamide, Vincristine, Gemcitabine, and Prednisolone in Patients With Cardiac Comorbidity: A United Kingdom National Cancer Research Institute Trial.
J. Clin. Oncol.
PUBLISHED: 11-12-2013
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The treatment of patients with diffuse large B-cell lymphoma (DLBCL) with cardiac comorbidity is problematic, because this group may not be able to receive anthracycline-containing chemoimmunotherapy. We designed a single-arm phase II multicenter trial of rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) in patients considered unfit for anthracycline-containing chemoimmunotherapy because of cardiac comorbidity.
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Endoscopic transmural drainage of pancreatic pseudocysts: technical challenges in the resource poor setting.
Case Rep Gastrointest Med
PUBLISHED: 09-26-2013
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Although surgical drainage of pancreatic pseudocysts has been superseded by less invasive options, the requirement for specialized equipment, technical expertise, and consumables limits the options available in low resource settings. We describe the challenges experienced during endoscopic transmural drainage in a low resource setting and the methods used to overcome these barriers. Despite operating in a low resource environment, endoscopic drainage of pancreatic pseudocysts can be incorporated into our armamentarium with minimal change to the existing hardware. Careful patient selection by a dedicated multidisciplinary team should be observed in order to achieve good outcomes.
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Identification in CLL of circulating intraclonal subgroups with varying B-cell receptor expression and function.
Blood
PUBLISHED: 08-16-2013
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Chronic lymphocytic leukemia (CLL) is a tumor of circulating B cells, variably stimulated and anergized following exposure to antigen in lymphoid tissues. Down-modulation of surface IgM (sIgM) occurs, but expression and signal capacity can recover in vitro and apparently in vivo during recirculation. We have now dissected individual circulating clones of CLL cases according to sIgM expression level by differential binding to bead-bound anti-IgM. Four clear subgroups (SG1-4) with increasing sIgM were identified in 37/37 cases. Engagement of sIgM induced phosphorylation of PLC?2 and ERK1/2 at levels ranging from very low in SG1 to high in SG4. Phosphorylation was suppressed by the BTK inhibitor ibrutinib. Expression of CXCR4 also increased from SG1 to SG4, but markers of previous activation and proliferation were dominant in SG1. Incubation of whole CLL populations in vitro led to striking increases in CXCR4 expression as well as recovery of sIgM. Clonal analysis reveals dynamic SGs following presumed antigen stimulation in tissues. SG4 represents a fully recovered, potentially dangerous population equipped to migrate to tissue and receive a proliferative stimulus. SG1 likely represents a postmitotic unresponsive "resting" population. The effect of ibrutinib on the small SG4 population may be the critical factor in therapeutic success.
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In vivo imaging of glucose uptake and metabolism in tumors.
Nat. Med.
PUBLISHED: 07-07-2013
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Tumors have a greater reliance on anaerobic glycolysis for energy production than normal tissues. We developed a noninvasive method for imaging glucose uptake in vivo that is based on magnetic resonance imaging and allows the uptake of unlabeled glucose to be measured through the chemical exchange of protons between hydroxyl groups and water. This method differs from existing molecular imaging methods because it permits detection of the delivery and uptake of a metabolically active compound in physiological quantities. We show that our technique, named glucose chemical exchange saturation transfer (glucoCEST), is sensitive to tumor glucose accumulation in colorectal tumor models and can distinguish tumor types with differing metabolic characteristics and pathophysiologies. The results of this study suggest that glucoCEST has potential as a useful and cost-effective method for characterizing disease and assessing response to therapy in the clinic.
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Vascular supply to the liver: a report of a rare arterial variant.
Case Rep Radiol
PUBLISHED: 07-04-2013
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In the classic description of hepatic arterial supply, the common hepatic artery originates from the coeliac trunk. However, there are numerous variations to this classic pattern. We report a rare variant pattern of hepatic arterial supply and discuss the clinical significance of this variation.
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Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.
N. Engl. J. Med.
PUBLISHED: 06-19-2013
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Brutons tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkins lymphoma, including mantle-cell lymphoma.
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C/EBP? suppresses senescence and inflammatory gene expression by heterodimerizing with C/EBP?.
Mol. Cell. Biol.
PUBLISHED: 06-17-2013
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C/EBP? is an important regulator of oncogene-induced senescence (OIS). Here, we show that C/EBP?, a heterodimeric partner of C/EBP? whose biological functions are not well understood, inhibits cellular senescence. Cebpg(-/-) mouse embryonic fibroblasts (MEFs) proliferated poorly, entered senescence prematurely, and expressed a proinflammatory gene signature, including elevated levels of senescence-associated secretory phenotype (SASP) genes whose induction by oncogenic stress requires C/EBP?. The senescence-suppressing activity of C/EBP? required its ability to heterodimerize with C/EBP?. Covalently linked C/EBP? homodimers (???) inhibited the proliferation and tumorigenicity of Ras(V12)-transformed NIH 3T3 cells, activated SASP gene expression, and recruited the CBP coactivator in a Ras-dependent manner, whereas ??? heterodimers lacked these capabilities and efficiently rescued proliferation of Cebpg(-/-) MEFs. C/EBP? depletion partially restored growth of C/EBP?-deficient cells, indicating that the increased levels of C/EBP? homodimers in Cebpg(-/-) MEFs inhibit proliferation. The proliferative functions of C/EBP? are not restricted to fibroblasts, as hematopoietic progenitors from Cebpg(-/-) bone marrow also displayed impaired growth. Furthermore, high CEBPG expression correlated with poorer clinical prognoses in several human cancers, and C/EBP? depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBP? neutralizes the cytostatic activity of C/EBP? through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes.
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An in silico structure-based approach to anti-infective drug discovery.
Parasitology
PUBLISHED: 06-17-2013
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SUMMARY In light of the low success rate of target-based genomics and HTS (High Throughput Screening) approaches in anti-infective drug discovery, in silico structure-based drug design (SBDD) is becoming increasingly prominent at the forefront of drug discovery. In silico SBDD can be used to identify novel enzyme inhibitors rapidly, where the strength of this approach lies with its ability to model and predict the outcome of protein-ligand binding. Over the past 10 years, our group have applied this approach to a diverse number of anti-infective drug targets ranging from bacterial D-ala-D-ala ligase to Plasmodium falciparum DHODH. Our search for new inhibitors has produced lead compounds with both enzyme and whole-cell activity with established on-target mode of action. This has been achieved with greater speed and efficiency compared with the more traditional HTS initiatives and at significantly reduced cost and manpower.
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Non-surgical pneumoperitoneum after oro-genital intercourse.
Int J Surg Case Rep
PUBLISHED: 06-10-2013
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In many cases, a pneumoperitoneum is due to air escaping from a perforated hollow viscus or surgical intervention but there are increasing reports of non-surgical causes.
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An integrative review and evidence-based conceptual model of the essential components of pre-service education.
Hum Resour Health
PUBLISHED: 05-20-2013
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With decreasing global resources, a pervasive critical shortage of skilled health workers, and a growing disease burden in many countries, the need to maximize the effectiveness and efficiency of pre-service education in low-and middle-income countries has never been greater.
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Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model.
Clin. Cancer Res.
PUBLISHED: 05-06-2013
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Neuroblastoma is one of the commonest extracranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here, we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models.
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Effective in-service training design and delivery: evidence from an integrative literature review.
Hum Resour Health
PUBLISHED: 05-02-2013
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In-service training represents a significant financial investment for supporting continued competence of the health care workforce. An integrative review of the education and training literature was conducted to identify effective training approaches for health worker continuing professional education (CPE) and what evidence exists of outcomes derived from CPE.
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Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles.
Lancet
PUBLISHED: 04-22-2013
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Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups.
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Novel antibodies targeting immune regulatory checkpoints for cancer therapy.
Br J Clin Pharmacol
PUBLISHED: 04-17-2013
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Cancers must evade or suppress the immune system in order to develop. Better understanding of the molecular regulation governing tumour detection and effective activation of the immune system (so called immune regulatory checkpoints) has provided new targets for cancer immunotherapy. Therapeutic monoclonal antibodies against these targets are currently undergoing clinical evaluation with more in pre-clinical development; buoyed by the recent licence approval of the anti-CTLA-4 antibody, ipilumumab, for use in melanoma. This article will review the current status of the various antibodies and target molecules being investigated.
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Vorinostat and bortezomib as third-line therapy in patients with advanced non-small cell lung cancer: a Wisconsin Oncology Network Phase II study.
Invest New Drugs
PUBLISHED: 04-13-2013
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Introduction The primary objective of this phase II trial was to evaluate the efficacy and tolerability of vorinostat and bortezomib as third-line therapy in advanced non-small cell lung cancer (NSCLC) patients. Methods Eligibility criteria included recurrent/metastatic NSCLC, having received 2 prior systemic regimens, and performance status 0-2. Patients took vorinostat 400 mg PO daily days 1-14 and bortezomib 1.3 mg/m2 IV day 1, 4, 8 and 11 in a 21-day cycle. Primary endpoint was 3-month progression free survival (3m-PFS), with a goal of at least 40 % of patients being free of progression at that time point. This study followed a two-stage minimax design. Results Eighteen patients were enrolled in the first stage. All patients had two prior lines of treatment. Patients received a median of two treatment cycles (range: 1-6) on study. There were no anti-tumor responses; stable disease was observed in 5 patients (27.8 %). Median PFS was 1.5 months, 3m-PFS rate 11.1 %, and median overall survival 4.7 months. The most common grade 3/4 toxicities were thrombocytopenia and fatigue. Two patients who had baseline taxane-related grade 1 peripheral neuropathy developed grade 3 neuropathy. The study was closed at its first interim analysis for lack of efficacy. Conclusions Bortezomib and vorinostat displayed minimal anti-tumor activity as third-line therapy in NSCLC. We do not recommend this regimen for further investigation in unselected patients.
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CD27 costimulation contributes substantially to the expansion of functional memory CD8(+) T cells after peptide immunization.
Eur. J. Immunol.
PUBLISHED: 03-28-2013
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Naive T cells require signals from multiple costimulatory receptors to acquire full effector function and differentiate to long-lived memory cells. The costimulatory receptor, CD27, is essential for optimal T-cell priming and memory differentiation in a variety of settings, although whether CD27 is similarly required during memory CD8(+) T-cell reactivation remains controversial. We have used OVA and anti-CD40 to establish a memory CD8(+) T-cell population and report here that their secondary expansion, driven by peptide and anti-CD40, polyI:C, or LPS, requires CD27. Furthermore, antigenic peptide and a soluble form of the CD27 ligand, CD70 (soluble recombinant CD70 (sCD70)), is sufficient for secondary memory CD8(+) T-cell accumulation at multiple anatomical sites, dependent on CD80/86. Prior to boost, resting effector- and central-memory CD8(+) T cells both expressed CD27 with greater expression on central memory cells. Nonetheless, both populations upregulated CD27 after TCR engagement and accumulated in proportion after boosting with Ag and sCD70. Mechanistically, sCD70 increased the frequency of divided and cytolytic memory T cells, conferred resistance to apoptosis and enabled retardation of tumor growth in vivo. These data demonstrate the central role played by CD27/70 during secondary CD8(+) T-cell activation to a peptide Ag, and identify sCD70 as an immunotherapeutic adjuvant for antitumor immunity.
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The effects of medication on cognition in long-term care.
Semin Speech Lang
PUBLISHED: 03-18-2013
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This article emphasizes the need to consider the role of medications when providing speech-language pathology services to a person with cognitive decline. This is particularly true when working with older adults. Many older adults take multiple medications that may have a direct effect on cognitive ability and as a result, on the success of rehabilitation efforts.
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The effect of over-commitment and reward on trapezius muscle activity and shoulder, head, neck, and torso postures during computer use in the field.
Am. J. Ind. Med.
PUBLISHED: 03-07-2013
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Because of reported associations of psychosocial factors and computer related musculoskeletal symptoms, we investigated the effects of a workplace psychosocial factor, reward, in the presence of over-commitment, on trapezius muscle activity and shoulder, head, neck, and torso postures during computer use.
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Time-lapse imaging of primary preneoplastic mammary epithelial cells derived from genetically engineered mouse models of breast cancer.
J Vis Exp
PUBLISHED: 02-22-2013
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Time-lapse imaging can be used to compare behavior of cultured primary preneoplastic mammary epithelial cells derived from different genetically engineered mouse models of breast cancer. For example, time between cell divisions (cell lifetimes), apoptotic cell numbers, evolution of morphological changes, and mechanism of colony formation can be quantified and compared in cells carrying specific genetic lesions. Primary mammary epithelial cell cultures are generated from mammary glands without palpable tumor. Glands are carefully resected with clear separation from adjacent muscle, lymph nodes are removed, and single-cell suspensions of enriched mammary epithelial cells are generated by mincing mammary tissue followed by enzymatic dissociation and filtration. Single-cell suspensions are plated and placed directly under a microscope within an incubator chamber for live-cell imaging. Sixteen 650 ?m x 700 ?m fields in a 4x4 configuration from each well of a 6-well plate are imaged every 15 min for 5 days. Time-lapse images are examined directly to measure cellular behaviors that can include mechanism and frequency of cell colony formation within the first 24 hr of plating the cells (aggregation versus cell proliferation), incidence of apoptosis, and phasing of morphological changes. Single-cell tracking is used to generate cell fate maps for measurement of individual cell lifetimes and investigation of cell division patterns. Quantitative data are statistically analyzed to assess for significant differences in behavior correlated with specific genetic lesions.
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Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design.
J. Med. Chem.
PUBLISHED: 02-22-2013
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?-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-? peptides, is an attractive target for the treatment of Alzheimers disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 ?M to 27 ?M following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.
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Antibody-peptide-MHC fusion conjugates target non-cognate T cells to kill tumour cells.
Cancer Immunol. Immunother.
PUBLISHED: 02-16-2013
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Attempts to generate robust anti-tumour cytotoxic T lymphocyte (CTL) responses using immunotherapy are frequently thwarted by exhaustion and anergy of CTL recruited to tumour. One strategy to overcome this is to retarget a population of virus-specific CTL to kill tumour cells. Here, we describe a proof-of-principle study using a bispecific conjugate designed to retarget ovalbumin (OVA)-specific CTL to kill tumour cells via CD20. A single-chain trimer (SCT) consisting of MHCI H-2K(b)/SIINFEKL peptide/beta 2 microglobulin/BirA was expressed in bacteria, refolded and chemically conjugated to one (1:1; F2) or two (2:1; F3) anti-hCD20 Fab fragments. In vitro, the [SCT × Fab] (F2 and F3) redirected SIINFEKL-specific OT-I CTL to kill CD20(+) target cells, and in the presence of CD20(+) target cells to provide crosslinking, they were also able to induce proliferation of OT-I cells. In vivo, activated OT-I CTL could be retargeted to kill [SCT × Fab]-coated B cells from hCD20 transgenic (hCD20 Tg) mice and also EL4 and B16 mouse tumour cells expressing human CD20 (hCD20). Importantly, in a hCD20 Tg mouse model, [SCT × Fab] administered systemically were able to retarget activated OT-I cells to deplete normal B cells, and their performance matched that of a bispecific antibody (BsAb) comprising anti-CD3 and anti-CD20. [SCT × Fab] were also active therapeutically in an EL4 tumour model. Furthermore, measurement of serum cytokine levels suggests that [SCT × Fab] are associated with a lower level of inflammatory cytokine release than the BsAb and so may be advantageous clinically in terms of reduced toxicity.
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Can early second-look tympanoplasty reduce the rate of conversion to modified radical mastoidectomy?
Acta Otolaryngol.
PUBLISHED: 02-05-2013
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Combined approach tympanoplasty (CAT) allows for successful treatment of cholesteatoma with rates of recurrent and residual disease comparable to open mastoid surgery. Early timing of second-look procedures allows easier removal of any recurrent or residual disease, which reduces the conversion rate to open mastoidectomy.
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Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Downs syndrome.
Nat. Med.
PUBLISHED: 02-01-2013
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Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that Snx27(-/-) mice have severe neuronal deficits in the hippocampus and cortex. Although Snx27(+/-) mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein ? (C/EBP?) in Downs syndrome brains and identify C/EBP? as a transcription factor for SNX27. Downs syndrome causes overexpression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBP?, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Downs syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Downs syndrome pathogenesis.
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The effect of overcommitment and reward on muscle activity, posture, and forces in the arm-wrist-hand region--a field study among computer workers.
Scand J Work Environ Health
PUBLISHED: 02-01-2013
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Office workers with high levels of overcommitment and low levels of reward are thought to be more prone to arm-wrist-hand symptoms, possibly through a higher internal physical exposure. The aim of this study was to examine the effects of high overcommitment and low reward on (i) forearm muscle activity, (ii) wrist posture and kinematics, and (iii) forces applied to computer input devices during computer work in an actual work setting.
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Competency-based education: the essential basis of pre-service education for the professional midwifery workforce.
Midwifery
PUBLISHED: 01-31-2013
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many articles published in the decade since promulgation of the Millennium Development Goals have acknowledged the distinct advantages to maternal and newborn health outcomes that can be achieved as a result of expanding access to skilled birth attendant (including midwifery) services. However, these advantages are often predicated on the assumption that the midwifery workforce shares a common definition and identity. Regrettably, a clear delineation of midwifery competencies is rarely addressed. A core set of midwifery competencies is essential to providing the high quality services that lead to the desirable health outcomes described in that body of research. Attribution of improved outcomes to access to midwifery cannot be made without a common understanding of a defined set of services provided to standard by the midwifery workforce across the inter-conceptional and childbearing time frame. The International Confederation of Midwives (ICM) has developed a clear list of competencies that delineate the domains of practice for the fully qualified, professional midwife. These domains frame the educational outcomes that must be conveyed within competency-based education programmes.
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Autologous stem cell transplantation for enteropathy-associated T-cell lymphoma: a retrospective study by the EBMT.
Blood
PUBLISHED: 01-29-2013
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Enteropathy-associated T-cell lymphoma (EATL) is a rare subtype of peripheral T-cell lymphomas with a poor prognosis. Autologous stem cell transplantation (ASCT) was retrospectively evaluated as a consolidation or salvage strategy for EATL. The analysis included 44 patients who received ASCT for EATL between 2000 and 2010. Thirty-one patients (70%) were in first complete or partial remission at the time of the ASCT. With a median follow-up of 46 months, relapse incidence, progression-free survival, and overall survival were 39%, 54%, and 59% at 4 years, respectively, with only one relapse occurring beyond 18 months posttransplant. There was a trend for better survival in patients transplanted in first complete or partial remission at 4 years (66% vs 36%; P = .062). ASCT is feasible in selected patients with EATL and can yield durable disease control in a significant proportion of the patients.
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Anthropometry-corrected exposure modeling as a method to improve trunk posture assessment with a single inclinometer.
J Occup Environ Hyg
PUBLISHED: 01-29-2013
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Measuring trunk posture in the workplace commonly involves subjective observation or self-report methods or the use of costly and time-consuming motion analysis systems (current gold standard). This work compared trunk inclination measurements using a simple data-logging inclinometer with trunk flexion measurements using a motion analysis system, and evaluated adding measures of subject anthropometry to exposure prediction models to improve the agreement between the two methods. Simulated lifting tasks (n=36) were performed by eight participants, and trunk postures were simultaneously measured with each method. There were significant differences between the two methods, with the inclinometer initially explaining 47% of the variance in the motion analysis measurements. However, adding one key anthropometric parameter (lower arm length) to the inclinometer-based trunk flexion prediction model reduced the differences between the two systems and accounted for 79% of the motion analysis methods variance. Although caution must be applied when generalizing lower-arm length as a correction factor, the overall strategy of anthropometric modeling is a novel contribution. In this lifting-based study, by accounting for subject anthropometry, a single, simple data-logging inclinometer shows promise for trunk posture measurement and may have utility in larger-scale field studies where similar types of tasks are performed.
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Fc?R??B controls the potency of agonistic anti-TNFR mAbs.
Cancer Immunol. Immunother.
PUBLISHED: 01-21-2013
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Isotype plays a crucial role in therapeutic monoclonal antibody (mAb) function, mediated in large part through differences in Fc? receptor (Fc?R) interaction. Monoclonal Abs such as rituximab and alemtuzumab, which bind target cells directly, are designed for efficient recruitment of immune effector cells through their activatory Fc?R engagement to mediate maximal target cell killing. In this setting, binding to inhibitory Fc?RIIB is thought to inhibit function, making mAbs with high activatory/inhibitory (A/I) Fc?R binding ratios, such as mouse IgG2a and human IgG1, the first choice for this role. In contrast, exciting new data show that agonistic mAbs directed against the tumour necrosis factor receptor superfamily member CD40 require interaction with Fc?RIIB for in vivo function. Such ligation activates antigen-presenting cells, promotes myeloid and CTL responses and potentially stimulates effective anti-cancer immunity. It appears that the role of Fc?RIIB is to mediate mAb hyper-crosslinking to allow CD40 downstream intracellular signalling. Previous work has shown that mAbs directed against other TNFR family members, Fas and death receptor 5 and probably death receptor 4, also require Fc?RIIB hyper-crosslinking to promote target cell apoptosis, suggesting a common mechanism of action. In mouse models, IgG1 is optimal for these agents as it binds to Fc?RIIB with tenfold higher affinity than IgG2a and hence has a relatively low A:I Fc?R binding ratio. In contrast, human IgG isotypes have a universally low affinity for Fc?RIIB, but in the case of human IgG1, engineering the Fc to increase its affinity for Fc?RIIB can potentially overcome this problem. Thus, modifying the A/I binding ratio of human IgG Fc can be used to optimise different types of therapeutic activity by enhancing cytotoxic or hyper-crosslinking function.
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Use of a biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilization: an analysis of mobilization and engraftment.
Br. J. Haematol.
PUBLISHED: 01-09-2013
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Peripheral blood haematopoietic progenitor cell mobilization has become a standard procedure prior to autologous stem cell transplantation. Biosimilar granulocyte colony-stimulating factors (GCSF) have recently been awarded European Union (EU) licences for stem cell mobilization but data for their use in this context remain limited. The biosimilar GCSF, Ratiograstim(®) (Ratiopharm, Ulm, Germany) was granted an EU licence in September 2008 and incorporated into clinical practice in the Wessex Blood and Marrow Transplantation Programme in December 2008. Data were retrospectively collected for 154 consecutive patients undergoing peripheral blood stem cell harvest between January 2009 and December 2011 using the biosimilar GCSF. 131 consecutive patients from the preceding 3 years, who had received Neupogen(®) , were used as a control. We analysed both parameters relevant to stem cell collection and engraftment data, where patients proceeded to transplantation. We found no statistically significant difference between the two groups when comparing CD34 predictors, total number of CD34(+) stem cells collected, number of days required for collection, or for time to engraftment. This is, to our knowledge, the largest direct comparison of a biosimilar GCSF with originator GCSF for stem cell mobilization. The use of biosimilar GCSF can produce a significant cost saving, allowing investment in other areas of stem cell transplantation.
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Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab.
J. Clin. Oncol.
PUBLISHED: 01-07-2013
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Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20(+)/CD22(+) B-cell non-Hodgkin lymphoma (NHL).
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Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 Randomized Study.
J. Clin. Oncol.
PUBLISHED: 01-07-2013
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Apart from localized gastric disease, there is no consensus on standard initial treatment of mucosa-associated lymphoid tissue lymphoma. The IELSG-19 study (Randomized Trial of Chlorambucil Versus Chlorambucil Plus Rituximab Versus Rituximab in MALT Lymphoma) was launched to compare chlorambucil alone versus chlorambucil plus rituximab in patients not previously given systemic anticancer therapy.
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Accessory renal arteries in a Caribbean population: a computed tomography based study.
Springerplus
PUBLISHED: 01-01-2013
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The commonest variation to the classic anatomic description of renal arterial supply is the presence of accessory renal arteries. The incidence varies widely according to ethnicity. There is no data on the prevalence of these anomalies in persons of Caribbean ethnicity.
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The new face of rheumatic heart disease in South West Nigeria.
Int J Gen Med
PUBLISHED: 01-01-2013
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To determine the current prevalence of rheumatic heart disease (RHD), clinical features, types of valvular lesions, complications and mortality, at Ladoke Akintola University of Technology (LAUTECH) Teaching Hospital, Osogbo, South West Nigeria.
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C5a-regulated CCAAT/enhancer-binding proteins ? and ? are essential in Fc? receptor-mediated inflammatory cytokine and chemokine production in macrophages.
J. Biol. Chem.
PUBLISHED: 12-06-2011
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CCAAT/enhancer-binding protein ? (C/EBP?) and C/EBP? are known to participate in the regulation of many genes associated with inflammation. However, little is known about the activation and function of C/EBP? and -? in inflammatory responses elicited by Fc? receptor (Fc?R) activation. Here we show that C/EBP? and -? activation are induced in IgG immune complex (IC)-treated macrophages. The increased expression of C/EBP? and -? occurred at both mRNA and protein levels. Furthermore, induction of C/EBP? and -? was mediated, to a large extent, by activating Fc?Rs. Using siRNA-mediated knockdown as well as macrophages deficient for C/EBP? and/or -?, we demonstrate that C/EBP? and -? play a critical role in the production of TNF-?, MIP-2, and MIP-1? in IgG IC-stimulated macrophages. Moreover, both ERK1/2 and p38 MAPK are involved in C/EBP induction and TNF-?, MIP-2, and MIP-1? production induced by IgG IC. We provide the evidence that C5a regulates IgG IC-induced inflammatory responses by enhancing ERK1/2 and p38 MAPK activities as well as C/EBP? and -? activities. Collectively, these data suggest that C/EBP? and -? are key regulators for Fc?R-mediated induction of cytokines and chemokines in macrophages. Furthermore, C/EBPs may play an important regulatory role in IC-associated inflammatory responses.
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Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results.
Haematologica
PUBLISHED: 11-04-2011
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Thalidomide is active in multiple myeloma and is associated with minimal myelosuppression, making it a good candidate for induction therapy prior to high-dose therapy with autologous stem-cell transplantation.
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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.

Video X seems to be unrelated to Abstract Y...

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.