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Find video protocols related to scientific articles indexed in Pubmed.
Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule.
J. Biol. Chem.
PUBLISHED: 11-14-2014
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Cancer-associated point mutations in isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) confer a neomorphic enzymatic activity: the reduction of alpha-ketoglutarate (?KG) to D-2-hydroxyglutaric acid (2HG), which is proposed to act as an oncogenic metabolite by inducing hypermethylation of histones and DNA. While selective inhibitors of mutant IDH1 and IDH2 have been identified and are currently under investigation as potential cancer therapeutics, the mechanistic basis for their selectivity is not yet well-understood. A high-throughput screen for selective inhibitors of IDH1 bearing the oncogenic mutation R132H identified Compound 1, a bis-imidazole phenol that inhibits 2HG production in cells. We investigated the mode of inhibition of Compound 1 and a previously published IDH1 mutant inhibitor with a different chemical scaffold. Steady-state kinetics and biophysical studies show that both of these compounds selectively inhibit mutant IDH1 by binding to an allosteric site, and that inhibition is competitive with respect to Mg(2+). A crystal structure of Compound 1 complexed with R132H IDH1 indicates that the inhibitor binds at the dimer interface and makes a direct contact with a residue involved in binding of the catalytically essential divalent cation. These results show that targeting a divalent cation binding residue can enable selective inhibition of mutant IDH1, and suggest that differences in magnesium binding between wild-type and mutant enzymes may contribute to the inhibitors' selectivity for the mutant enzyme.
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Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene ?-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors.
J. Med. Chem.
PUBLISHED: 11-13-2014
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The optimization of a series of aminooxazoline xanthene inhibitors of ?-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust A? lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust A? reduction in a rat pharmacodynamic model (78% A? reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.
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Inhibitors of ?-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718).
J. Med. Chem.
PUBLISHED: 11-04-2014
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We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain A? levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.
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Quality of diabetes care worldwide and feasibility of implementation of the Alphabet Strategy: GAIA project (Global Alphabet Strategy Implementation Audit).
BMC Health Serv Res
PUBLISHED: 09-22-2014
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The Alphabet Strategy (AS) is a diabetes care checklist ensuring "important, simple things are done right all the time." Current audits of diabetes care in developed countries reveal wide variations in quality with performance of care processes frequently sub-optimal. This study had three components:• an audit to assess diabetes care quality worldwide,• a questionnaire study seeking opinions on the merits of the AS,• a pilot study to assess the practicality of implementation of the AS in a low socioeconomic setting.
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Comparison of amplicor and GeneXpert MTB/RIF tests for diagnosis of tuberculous meningitis.
J. Clin. Microbiol.
PUBLISHED: 07-23-2014
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There are no data about the comparative accuracy of commercially available nucleic acid amplification tests (GeneXpert MTB/RIF and Roche Amplicor) for the diagnosis of tuberculous meningitis (TBM). A total of 148 patients with suspected TBM were evaluated, and cultures served as the reference standard. The sensitivities and specificities (95% confidence interval [CI]) for the Amplicor and Xpert MTB/RIF tests were similar: 46 (31-60) versus 50 (33-67) and 99 (93-100) and 94 (84-99), respectively.
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PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene.
Blood
PUBLISHED: 07-08-2014
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Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in CD25-positive AML.
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Vitamin B12 deficiency is associated with adverse lipid profile in Europeans and Indians with type 2 diabetes.
Cardiovasc Diabetol
PUBLISHED: 07-03-2014
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Metformin, a standard therapy in type 2 diabetes, reduces vitamin B12 levels. Studies linking low vitamin B12 levels and cardiovascular disease are equivocal and suggest improving B12 levels may help in primary prevention. The role of vitamin B12 deficiency on cardiovascular risk factors, especially in type 2 diabetes has not been explored. The aim of this study is to investigate whether vitamin B12 deficiency in type 2 diabetes patients is associated with cardiovascular risk factors in two different ethnic groups in UK and India.
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Combination of PIM and JAK2 inhibitors synergistically suppresses MPN cell proliferation and overcomes drug resistance.
Oncotarget
PUBLISHED: 05-17-2014
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Inhibitors of JAK2 kinase are emerging as an important treatment modality for myeloproliferative neoplasms (MPN). However, similar to other kinase inhibitors, resistance to JAK2 inhibitors may eventually emerge through a variety of mechanisms. Effective drug combination is one way to enhance therapeutic efficacy and combat resistance against JAK2 inhibitors. To identify potential combination partners for JAK2 compounds in MPN cell lines, we performed pooled shRNA screen targeting 5,000 genes in the presence or absence of JAK2 blockade. One of the top hits identified was MYC, an oncogenic transcription factor that is difficult to inhibit directly, but could be targeted by modulation of upstream regulatory elements such as kinases. We demonstrate herein that PIM kinase inhibitors efficiently suppress MYC protein levels in MPN cell lines. Importantly, overexpression of MYC restores the viability of PIM inhibitor-treated cells, revealing causal relationship between MYC down-regulation and cell growth inhibition by PIM compounds. Combination of various PIM inhibitors with a JAK2 inhibitor results in significant synergistic growth inhibition of multiple MPN cancer cell lines and induction of apoptosis. Mechanistic studies revealed strong downregulation of phosphorylated forms of S6 and 4EBP1 by JAK2/PIM inhibitor combination treatment. Finally, such combination was effective in eradicating in vitro JAK2 inhibitor-resistant MPN clones, where MYC is consistently up-regulated. These findings demonstrate that simultaneous suppression of JAK2 and PIM kinase activity by small molecule inhibitors is more effective than either agent alone in suppressing MPN cell growth. Our data suggest that JAK2 and PIM combination might warrant further investigation for the treatment of JAK2-driven hematologic malignancies.
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Determinants of PCR performance (Xpert MTB/RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments.
Sci Rep
PUBLISHED: 05-09-2014
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The determinants of Xpert MTB/RIF sensitivity, a widely used PCR test for the diagnosis of tuberculosis (TB) are poorly understood. We compared culture time-to-positivity (TTP; a surrogate of bacterial load), MTB/RIF TB-specific and internal positive control (IPC)-specific C(T) values, and clinical characteristics in patients with suspected TB who provided expectorated (n = 438) or induced sputum (n = 128), tracheal aspirates (n = 71), bronchoalveolar lavage fluid (n = 152), pleural fluid (n = 76), cerebral spinal fluid (CSF; n = 152), pericardial fluid (n = 131), or urine (n = 173) specimens. Median bacterial load (TTP in days) was the strongest associate of MTB/RIF positivity in each fluid. TTP correlated with C(T) values in pulmonary specimens but not extrapulmonary specimens (Spearman's coefficient 0.5043 versus 0.1437; p = 0.030). Inhibition affected a greater proportion of pulmonary specimens than extrapulmonary specimens (IPC C(T) > 34: 6% (47/731) versus 1% (4/381; p < 0.0001). Pulmonary specimens had greater load than extrapulmonary specimens [TTPs (interquartile range) of 11 (7-16) versus 22 (18-33.5) days; p < 0.0001]. HIV-infection was associated with a decreased likelihood of MTB/RIF-positivity in pulmonary specimens but an increased likelihood in extrapulmonary specimens. Mycobacterial load, which displays significant variation across different body compartments, is the main determinant of MTB/RIF-positivity rather than PCR inhibition. MTB/RIF C(T) is a poor surrogate of load in extrapulmonary specimens.
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Histological evaluation of mandibular third molar roots retrieved after coronectomy.
Br J Oral Maxillofac Surg
PUBLISHED: 02-20-2014
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There is a resurgence of interest in coronectomy for the management of mandibular third molars because it has a low risk of injury to the inferior dental nerve. However, there is concern that the root that is left in place will eventually become a source of infection. We describe the histological evaluation of 26 consecutive symptomatic coronectomy roots in 21 patients. All roots had vital tissue in the pulp chamber and there was no evidence of periradicular inflammation. Persistent postoperative symptoms related predominantly to inflammation of the soft tissue, which was caused by partially erupted roots or failure of the socket to heal.
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TRIM5? and TRIM22 are differentially regulated according to HIV-1 infection phase and compartment.
J. Virol.
PUBLISHED: 01-29-2014
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The antiviral role of TRIM E3 ligases in vivo is not fully understood. To test the hypothesis that TRIM5? and TRIM22 have differential transcriptional regulation and distinct anti-HIV roles according to infection phase and compartment, we measured TRIM5?, TRIM22, and type I interferon (IFN-I)-inducible myxovirus resistance protein A (MxA) levels in peripheral blood mononuclear cells (PBMCs) during primary and chronic HIV-1 infection, with chronic infection samples being matched PBMCs and central nervous system (CNS)-derived cells. Associations with biomarkers of disease progression were explored. The impact of IFN-I, select proinflammatory cytokines, and HIV on TRIM E3 ligase-specific expression was investigated. PBMCs from individuals with primary and chronic HIV-1 infection had significantly higher levels of MxA and TRIM22 than did PBMCs from HIV-1-negative individuals (P < 0.05 for all comparisons). PBMCs from chronic infection had lower levels of TRIM5? than did PBMCs from primary infection or HIV-1-uninfected PBMCs (P = 0.0001 for both). In matched CNS-derived samples and PBMCs, higher levels of MxA (P = 0.001) and TRIM5? (P = 0.0001) in the CNS were noted. There was a negative correlation between TRIM22 levels in PBMCs and plasma viral load (r = -0.40; P = 0.04). In vitro, IFN-I and, rarely, proinflammatory cytokines induced TRIM5? and TRIM22 in a cell type-dependent manner, and the knockdown of either protein in CD4(+) lymphocytes resulted in increased HIV-1 infection. These data suggest that there are infection-phase-specific and anatomically compartmentalized differences in TRIM5? and TRIM22 regulation involving primarily IFN-I and specific cell types and indicate subtle differences in the antiviral roles and transcriptional regulation of TRIM E3 ligases in vivo.
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Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study.
PLoS Med.
PUBLISHED: 10-01-2013
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Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM.
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Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches.
J. Biol. Chem.
PUBLISHED: 09-03-2013
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PRP4 kinase is known for its roles in regulating pre-mRNA splicing and beyond. Therefore, a wider spectrum of PRP4 kinase substrates could be expected. The role of PRP4 kinase in cancer is also yet to be fully elucidated. Attaining specific and potent PRP4 inhibitors would greatly facilitate the study of PRP4 biological function and its validation as a credible cancer target. In this report, we verified the requirement of enzymatic activity of PRP4 in regulating cancer cell growth and identified an array of potential novel substrates through orthogonal proteomics approaches. The ensuing effort in structural biology unveiled for the first time unique features of PRP4 kinase domain and its potential mode of interaction with a low molecular weight inhibitor. These results provide new and important information for further exploration of PRP4 kinase function in cancer.
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To retrieve or not to retrieve the coronectomy root--the clinical dilemma.
Dent Update
PUBLISHED: 08-06-2013
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Coronectomy of mandibular third molars is a well established technique that is going through a resurgence as it seems to reduce the risk of inferior dental nerve (IDN) injury. The reservation with the technique arises because of fear that the retained root will become infected and symptomatic over time. General dental practitioners will be responsible for the long-term review and care of these patients and, consequently, it is important that they are aware of the technique and its sequelae. Clinical Relevance: Coronectomy of mandibular third molars to avoid nerve injury is becoming increasingly popular. It is important that general dental practitioners (GDPs) are aware of the immediate and later sequelae of treatment and the implication of the retained root.
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Hydroxyethylamine-based inhibitors of BACE1: P?-P? macrocyclization can improve potency, selectivity, and cell activity.
Bioorg. Med. Chem. Lett.
PUBLISHED: 04-02-2013
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We describe a systematic study of how macrocyclization in the P?-P? region of hydroxyethylamine-based inhibitors of ?-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid ?-peptide (A?)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.
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Unerupted teeth associated with dentigerous cysts and treated with coronectomy: mini case series.
Br J Oral Maxillofac Surg
PUBLISHED: 02-25-2013
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There is a resurgence of interest in coronectomy, but its appropriate application in the management of third molar teeth has yet to be defined. Dentigerous cysts associated with unerupted teeth are most commonly associated with mandibular third molars. In this case series we evaluate outcome after coronectomy of teeth with associated dentigerous cysts in cases where the inferior dental nerve was thought to be at risk, or there was an increased risk of mandibular fracture. We retrospectively studied 21 consecutive patients treated by coronectomy for dentigerous cysts at the Oral Surgery Department at Guys Hospital. The most commonly affected teeth were mandibular third molars (20/21). One patient had permanent injury to the inferior dental nerve, but no mandibular fracture or recurrence of cyst was reported. One patient required secondary retrieval of the retained root because of eruption. Coronectomy of unerupted teeth associated with dentigerous cysts is an effective treatment when there is high risk of injury to the inferior dental nerve injury or potential for mandibular fracture. Further work with larger numbers and longer follow-up is required to discover the long-term outcome of the electively retained root.
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The impacts of "growing our own": a pilot project to address health disparities by training health professionals to become certified diabetes educators in safety net practices.
Diabetes Educ
PUBLISHED: 12-06-2011
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The purpose of the study was to examine the impact of incorporating certified diabetes educator trainees into medical practices on patient diabetes outcomes.
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Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists.
Bioorg. Med. Chem. Lett.
PUBLISHED: 10-28-2011
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Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.
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Comparative utility of cytokine levels and quantitative RD-1-specific T cell responses for rapid immunodiagnosis of tuberculous meningitis.
J. Clin. Microbiol.
PUBLISHED: 08-31-2011
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The rapid diagnosis of tuberculous meningitis (TBM) is problematic. We found in 150 patients with suspected TBM that, similar to RD-1-specific quantitative cerebrospinal fluid (CSF) T-cell responses, unstimulated CSF gamma interferon (IFN-?) levels when used together with other rapid confirmatory tests (Gram stain and cryptococcal latex agglutination test) may allow the accurate and rapid diagnosis of TBM in a setting in which tuberculosis (TB) and HIV are endemic. In resource-poor settings, a clinical prediction rule (CPR) may be useful to clinicians, and thus the IFN-? assay may potentially need to be used only when the clinical score is below a prespecified threshold. These preliminary findings will need to be confirmed in further studies.
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Identification of a potent, state-dependent inhibitor of Nav1.7 with oral efficacy in the formalin model of persistent pain.
J. Med. Chem.
PUBLISHED: 06-02-2011
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Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.
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Visfatin is regulated by rosiglitazone in type 2 diabetes mellitus and influenced by NF?B and JNK in human abdominal subcutaneous adipocytes.
PLoS ONE
PUBLISHED: 04-28-2011
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Visfatin has been proposed as an insulin-mimicking adipocytokine, predominantly secreted from adipose tissue and correlated with obesity. However, recent studies suggest visfatin may act as a proinflammatory cytokine. Our studies sought to determine the significance of this adipocytokine and its potential role in the pathogenesis of T2DM. Firstly, we examined the effects of diabetic status on circulating visfatin levels, and several other adipocytokines, demonstrating that diabetic status increased visfatin*, TNF-?*** and IL-6*** compared with non-diabetic subjects (*p<0.05, **p<0.01, ***p<0.001, respectively). We then assessed the effects of an insulin sensitizer, rosiglitazone (RSG), in treatment naïve T2DM subjects, on circulating visfatin levels. Our findings showed that visfatin was reduced post-RSG treatment [vs. pre-treatment (*p<0.05)] accompanied by a reduction in HOMA-IR**, thus implicating a role for insulin in visfatin regulation. Further studies addressed the intracellular mechanisms by which visfatin may be regulated, and may exert pro-inflammatory effects, in human abdominal subcutaneous (Abd Sc) adipocytes. Following insulin (Ins) and RSG treatment, our in vitro findings highlighted that insulin (100 nM), alone, upregulated visfatin protein expression whereas, in combination with RSG (10 nM), it reduced visfatin*, IKK?** and p-JNK1/2*. Furthermore, inhibition of JNK protein exacted a significant reduction in visfatin expression (**p<0.01), whilst NF-?B blockade increased visfatin (*p<0.05), thus identifying JNK as the more influential factor in visfatin regulation. Additional in vitro analysis on adipokines regulating visfatin showed that only Abd Sc adipocytes treated with recombinant human (rh)IL-6 increased visfatin protein (*p<0.05), whilst rh visfatin treatment, itself, had no influence on TNF-?, IL-6 or resistin secretion from Sc adipocytes. These data highlight visfatins regulation by insulin and RSG, potentially acting through NF-?B and JNK mechanisms, with only rh IL-6 modestly affecting visfatin regulation. Taken together, these findings suggest that visfatin may represent a pro-inflammatory cytokine that is influenced by insulin/insulin sensitivity via the NF-?B and JNK pathways.
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Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines.
Cancer Res.
PUBLISHED: 10-08-2010
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In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.
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Comparison of a clinical prediction rule and a LAM antigen-detection assay for the rapid diagnosis of TBM in a high HIV prevalence setting.
PLoS ONE
PUBLISHED: 09-30-2010
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The diagnosis of tuberculous meningitis (TBM) in resource poor TB endemic environments is challenging. The accuracy of current tools for the rapid diagnosis of TBM is suboptimal. We sought to develop a clinical-prediction rule for the diagnosis of TBM in a high HIV prevalence setting, and to compare performance outcomes to conventional diagnostic modalities and a novel lipoarabinomannan (LAM) antigen detection test (Clearview-TB®) using cerebrospinal fluid (CSF).
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Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.
J. Med. Chem.
PUBLISHED: 08-06-2010
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The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
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Three-dimensional transthoracic echocardiography in identification of aorto-right atrial fistula and aorto-right ventricular fistulas.
Echocardiography
PUBLISHED: 06-30-2010
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We report the case of a 72-year-old woman who developed new onset right ventricular failure after redo aortic valve replacement. The diagnosis of left to right shunt was initially made using two-dimensional transthoracic echocardiography (2DTTE) and 2D transesophageal echo with color Doppler (TEE). Definite diagnosis of aorto-right atrial and aorto-right ventricular fistula was made using three-dimensional transthoracic echocardiography (3DTTE) with color flow Doppler imaging. Early recognition and diagnosis of this rare surgical complication is imperative for prompt surgical repair of this lethal defect. 3DTTE should be utilized in cases of new onset heart failure with unclear etiology to diagnose unusual causes of this potentially fatal condition.
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Bisphosphonate osteonecrosis of the jaw: a literature review of UK policies versus international policies on the management of bisphosphonate osteonecrosis of the jaw.
Br J Oral Maxillofac Surg
PUBLISHED: 06-27-2010
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Despite the increasing number of cases of osteonecrosis of the jaws related to bisphosphonate therapy described in the literature there is a paucity of evidence-based treatment for the condition. In this second article on bisphosphonate-related jaw complications we discuss the different treatment strategies for the condition, review current literature, particularly in relation to the recommendations that have been published, and discuss the evidence behind them.
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Cerebrospinal T-cell responses aid in the diagnosis of tuberculous meningitis in a human immunodeficiency virus- and tuberculosis-endemic population.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 05-04-2010
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Current tools for the rapid diagnosis of tuberculous meningitis (TBM) are suboptimal. We evaluated the clinical utility of a quantitative RD-1 IFN-gamma T-cell enzyme-linked immunospot (ELISPOT) assay (T-SPOT.TB), using cerebrospinal fluid cells for the rapid immunodiagnosis of TBM.
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Bisphosphonate osteonecrosis of the jaw--a literature review of UK policies versus international policies on bisphosphonates, risk factors and prevention.
Br J Oral Maxillofac Surg
PUBLISHED: 02-04-2010
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There has been an exponential rise in the literature of osteonecrosis and its complications in patients taking bisphosphonate drugs. Despite this increase, there is little evidence-based publications on how best to manage this complication. In this article (the first of two on bisphosphonate related jaw complications), we compare the guidelines produced by national specialist medical associations and expert panels on the prevention of bisphosphonate osteonecrosis of the jaws and review the evidence behind these guidelines.
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Utility of a novel lipoarabinomannan assay for the diagnosis of tuberculous meningitis in a resource-poor high-HIV prevalence setting.
Cerebrospinal Fluid Res
PUBLISHED: 07-03-2009
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In Africa, tuberculous meningitis (TBM) is an important opportunistic infection in HIV-positive patients. Current diagnostic tools for TBM perform sub-optimally. In particular, the rapid diagnosis of TBM is challenging because smear microscopy has a low yield and PCR is not widely available in resource-poor settings.
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Trastuzumab-induced cardiomyopathy: not as benign as it looks? A retrospective study.
J. Card. Fail.
PUBLISHED: 04-30-2009
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One of the recent advances in the treatment of breast cancer is trastuzumab. However, a major side effect of this medication is cardiomyopathy. Our objective was to determine the incidence of trastuzumab-induced cardiomyopathy and the rate of discontinuation of trastuzumab in a clinical setting.
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Diagnosis of acute malaria by laser based cell counter with comparison of conventional and recent techniques in Indian scenario.
Indian J Pathol Microbiol
PUBLISHED: 04-01-2009
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Malaria is one of the most important parasitic diseases in humans affecting 103 countries worldwide.
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Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase.
Bioorg. Med. Chem. Lett.
PUBLISHED: 03-03-2009
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Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase.
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Isolated thyroxine malabsorption treated with intramuscular thyroxine injections.
Am. J. Med. Sci.
PUBLISHED: 02-14-2009
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An 18-year-old girl with multiple autoimmune endocrinopathies was referred to the endocrinology clinic for management of hypothyroidism. She required increasing doses of thyroxine but remained hypothyroid. Daily and weekly supervised thyroxine administration strategies were unsuccessful. She was extensively investigated for malabsorption; however, all the results were normal. She was subsequently commenced on weekly intramuscular thyroxine injections and became biochemically and clinically euthyroid. Subsequent elective hospital admission and administration of thyroxine via nasogastric tube resulted in recurrence of her hypothyroidism. This case demonstrates apparent isolated true levothyroxine malabsorption existing in isolation and suggests that intramuscular thyroxine injections may be a useful therapeutic modality in these patients.
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Actinic granuloma affecting the upper lip: a rare and challenging clinical entity.
Br J Oral Maxillofac Surg
PUBLISHED: 02-08-2009
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Actinic granuloma is a rare dermatological condition that can be difficult to diagnose, and the opinion of specialist dermatologists and histopathologists might be needed to confirm diagnosis. Our patients lesion was not diagnosed until 3 years after initial presentation. We are aware of only 18 reported cases since 1982, and to our knowledge this is the first reported to affect the upper lip. The condition is slow to improve, and the most effective treatment remains unclear. We used intralesional steroid injections, but a small area has yet to resolve 9 years after presentation.
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Discovery of alpha-amidosulfones as potent and selective agonists of CB2: synthesis, SAR, and pharmacokinetic properties.
Bioorg. Med. Chem. Lett.
PUBLISHED: 01-29-2009
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A series of alpha-amidosulfones were found to be potent and selective agonists of CB(2). The discovery, synthesis, and structure-activity relationships of this series of agonists are reported. In addition, the pharmacokinetic properties of the most promising compounds are profiled.
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Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors.
Clin. Cancer Res.
PUBLISHED: 01-02-2009
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Angiogenesis plays a critical role in breast cancer development and progression. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates endothelial cell proliferation and survival. We investigated the effects of motesanib, a novel, oral inhibitor of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit receptor, on the growth of xenografts representing various human breast cancer subtypes.
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Effects of structural and electronic characteristics of chalcones on the activation of peroxisome proliferator-activated receptor gamma.
Chem. Pharm. Bull.
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Chalcones share some structural similarities with GW-1929, a highly-selective and potent agonist for peroxisome proliferator-activated receptor-gamma (PPAR?). In this study, we tested 53 structurally diverse chalcones to identify characteristics essential for PPAR? activation in a GAL4-based transactivation assay. This screen identified several novel chalcone agonists of PPAR?. Our results indicate that chalcones with an electron rich group or sterically large groups such as naphthyl on the carbonyl side tend to activate PPAR?. The absence of any strict structural or electronic requirements suggests that the flexibility of the PPAR? ligand binding pocket may allow binding of diverse chalcones with some preference for a slightly larger electron-rich group on the carbonyl side. We predict that further structure-activity relationship studies on chalcones with naphthalene or electron-rich groups near the carbonyl moiety will lead to the development of more potent PPAR? agonists.
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Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and CNS penetrable BACE inhibitors for the treatment of Alzheimers disease.
J. Med. Chem.
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A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human ?-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS A?40 in naive rats.
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2-Phenylamino-6-cyano-1H-benzimidazole-based isoform selective casein kinase 1 gamma (CK1?) inhibitors.
Bioorg. Med. Chem. Lett.
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Screening of the Amgen compound library led to the identification of 2-phenylamino-6-cyano-1H-benzimidazole 1a as a potent CK1 gamma inhibitor with excellent kinase selectivity and unprecedented CK1 isoform selectivity. Further structure-based optimization of this series resulted in the discovery of 1h which possessed good enzymatic and cellular potency, excellent CK1 isoform and kinase selectivity, and acceptable pharmacokinetic properties.
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Coronectomy practice. Paper 2: complications and long term management.
Br J Oral Maxillofac Surg
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Coronectomy was developed to reduce the incidence of iatrogenic injury to the inferior dental nerve, which can be a result of routine mandibular third molar surgery, but it is not widely accepted despite early studies that all showed positive results. This two-part paper looks at the technique in more detail to help clinicians gain a better understanding of the procedure. The first part dealt in detail with technical aspects. This one will consider the management of common complications.
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Structure guided P1 modifications of HEA derived ?-secretase inhibitors for the treatment of Alzheimers disease.
Bioorg. Med. Chem. Lett.
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The synthesis and SAR of a series of BACE-1 hydroxyethyl amine inhibitors containing substitutions on a spirocyclobutyl moiety is described. Selectivity against cathepsin D, a related aspartyl protease with potential off target toxicity, and improved microsomal stability is exemplified.
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Design and synthesis of potent, orally efficacious hydroxyethylamine derived ?-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.
J. Med. Chem.
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We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-? peptide (A?) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of A? levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1.
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Design and preparation of a potent series of hydroxyethylamine containing ?-secretase inhibitors that demonstrate robust reduction of central ?-amyloid.
J. Med. Chem.
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A series of potent hydroxyethyl amine (HEA) derived inhibitors of ?-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS ?-amyloid (A?) in Sprague-Dawley rats following oral administration.
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Synthesis of 4-substituted chlorophthalazines, dihydrobenzoazepinediones, 2-pyrazolylbenzoic acid, and 2-pyrazolylbenzohydrazide via 3-substituted 3-hydroxyisoindolin-1-ones.
J. Org. Chem.
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Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, N,N-dimethylaminophthalimide (8a) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones 9b, 9i-9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b-1v via reaction with hydrazine, followed by chlorination with POCl(3). We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to N,N-dimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a-15c via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids 16a-16d and 2-pyrazolyl benzohydrazides 17a-17g rather than the expected alkynyl phthalazinones.
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Coronectomy practice. Paper 1. Technique and trouble-shooting.
Br J Oral Maxillofac Surg
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Coronectomy is a technique that reduces morbidity of the nerve after operation on high-risk mandibular third molars. This two-part paper aims to give an overview of the technique and a description of common problems that can be encountered during and after operation. In this paper we discuss the technique as an overview and then each type of impaction more specifically. We also explore common problems encountered during the procedure and their subsequent management.
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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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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.