JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity: a literature review.
Expert Opin Drug Metab Toxicol
PUBLISHED: 11-18-2014
Show Abstract
Hide Abstract
Introduction: Existing clinical evidence indicates that many tyrosine kinase inhibitors (TKIs) are associated with idiosyncratic hepatotoxicity. TKIs possess risk factors for developing drug-induced liver injury such as their high daily dose, being substrates of P450 enzyme and being involved in significant hepatic metabolism. Several successful strategies to overcome TKI-induced hepatotoxicity include: switching to an alternative TKI with a similar mechanism of action, using an alternative dose and introduction of corticosteroids for treatment and prevention of hepatotoxicity. Areas covered: This review highlights the formation of reactive metabolites and how this leads to toxicity, as well as the current clinical management of TKI-induced hepatotoxicity. Expert opinion: Numerous events need to occur in an individual patient before converging into an idiosyncratic hepatotoxicity episode. Of these, the formation of a reactive intermediate through metabolism appears to be the prerequisite. This critical event involves an intricate chemico-biological interaction where, on one hand, drug-specific characteristics create the propensity for occurrence and, on the other hand, patient risk factors determine the individuality of response. With improved understanding of the mechanisms leading to adverse events, several strategies are being adopted to prevent and treat TKI-induced hepatotoxicity. However, further evidence is required before they can be recommended to larger populations.
Related JoVE Video
Oncogene addiction and immunity: clinical implications of tumour infiltrating lymphocytes in breast cancers overexpressing the HER2/neu oncogene.
Curr Opin Oncol
PUBLISHED: 09-05-2014
Show Abstract
Hide Abstract
To review the evidence that correlates tumour infiltrating lymphocytes, a surrogate biomarker of pre-existing host antitumour immunity, and survival in HER2-overexpressing breast cancers. This is of particular relevance to developing immune biomarkers and harnessing new immunotherapeutics in this breast cancer subtype.
Related JoVE Video
Metabolism-related pharmacokinetic drug-drug interactions in tyrosine kinase inhibitors: current understanding, challenges and recommendations.
Br J Clin Pharmacol
PUBLISHED: 08-14-2014
Show Abstract
Hide Abstract
Drug-drug interactions (DDIs) occur when a patient's response to the drug is modified by administration or co-exposure to another drug. The main cytochrome P450 (CYP) enzyme, CYP3A4, is implicated in the metabolism of almost all of the tyrosine kinase inhibitors (TKIs). Therefore, there is a substantial potential for interaction between TKIs and other drugs that modulate the activity of this metabolic pathway. Cancer patients are susceptible to DDIs as they receive many medications, either for supportive care or for treatment of toxicity. Differences in DDI outcomes are generally negligible because of the wide therapeutic window of common drugs; however for anticancer agents, serious clinical consequences may occur from small changes in drug metabolism and pharmacokinetics. Therefore, the objective of this review is to highlight the current understanding of DDIs among TKIs, with a focus on metabolism, as well as to identify challenges in the prediction of DDIs and provide recommendations.
Related JoVE Video
Effects of adding resorbable phosphate glass fibres and PLA to calcium phosphate bone cements.
J Appl Biomater Funct Mater
PUBLISHED: 04-06-2014
Show Abstract
Hide Abstract
ABSTRACTBackground: Calcium phosphate cements (CPCs), due to their biocompatibility and degradation properties, are being widely investigated as a replacement to more commonly used polymethylmethacrylate (PMMA) for vertebroplasty. CPCs have shown the potential to be replaced by host bone tissue during the healing/remodelling process. However, brittleness and comparatively low strength restrict the use of CPC in load-bearing applications. Although porous CPC can integrate with bone over time, slow degradation profiles and poor interconnectivity between pores restricts osseointegration to the top layer of CPC only.Methods: Polylactic acid (PLA) and phosphate glass fibres (PGFs) were incorporated in a CPC matrix to overcome the problem of inherent brittleness and limited osseointegration.Results: Incorporation of PLA and PGFs within CPC was successful in achieving a much less brittle CPC matrix without affecting the mechanical properties of CPC. The area under the stress-strain curve showed that the total energy to failure of the CPC hybrid was significantly greater than that of the CPC control.Conclusions: The methodology adopted here to add PLA within the CPC matrix may also allow for incorporation of PLA cross-linked biochemicals. Micrographic studies revealed that it was possible to confer control over pore size, shape and interconnectivity without negatively affecting the mechanical properties of the cement. This tailorable porosity could potentially lead to better osseointegration within CPC.
Related JoVE Video
An improved reference measurement procedure for triglycerides and total glycerides in human serum by isotope dilution gas chromatography-mass spectrometry.
Clin. Chim. Acta
PUBLISHED: 02-01-2014
Show Abstract
Hide Abstract
Triglycerides are widely tested in clinical laboratories using enzymatic methods for lipid profiling. As enzymatic methods can be affected by interferences from biological samples, this together with the non-specific nature of triglycerides measurement makes it necessary to verify the accuracy of the test results with a reference measurement procedure. Several such measurement procedures had been published. These procedures generally involved lengthy and laborious sample preparation steps. In this paper, an improved reference measurement procedure for triglycerides and total glycerides was reported which simplifies the sample preparation steps and greatly shortens the time taken.
Related JoVE Video
Integrin linked kinase (ILK) is required for lens epithelial cell survival, proliferation and differentiation.
Exp. Eye Res.
PUBLISHED: 01-10-2014
Show Abstract
Hide Abstract
While the role of growth factors in lens development has been investigated extensively, the role of extracellular matrix signalling is less well understood. The developing lens expresses predominantly laminin-binding integrins (such as ?3?1, ?6?1), which are cooperatively required in the lens epithelium during development. We investigated the role of ILK, a downstream mediator of integrin signalling in mice conditionally null for Ilk. Mutant lenses showed epithelial thinning at E17.5 with reduced proliferation and epithelial cell number and aberrant fibre differentiation. There was complete loss of the central epithelium from postnatal day (P) 2 due to cell death followed by fibre cell degeneration and death by P10 as well as rupture of the lens capsule between P10 and P21. At E17.5 there was significant inhibition (?50%) of epithelial cell cycle progression, as shown by BrdU incorporation, cyclin D1/D2 and phospho-histone H3 immunostaining. The epithelial marker, E-cadherin, was decreased progressively from E17.5 to P2, in the central epithelium, but there was no significant change in Pax6 expression. Analyses of ERK and Akt phosphorylation indicated marked depression of MAPK and PI3K-Akt signalling, which correlated with decreased phosphorylation of FRS2? and Shp2, indicating altered activation of FGF receptors. At later postnatal stages there was reduced or delayed expression of fibre cell markers (?-crystallin and p57(kip2)). Loss of Ilk also affected deposition of extracellular matrix, with marked retention of collagen IV within differentiating fibre cells. By quantitative RT-PCR array there was significantly decreased expression of 19 genes associated with focal adhesions, actin filament stability and MAPK and PI3K/Akt signalling. Overall, these data indicate that ILK is required for complete activation of signalling cascades downstream of the FGF receptor in lens epithelium and fibre cells during development and thus is involved in epithelial proliferation, survival and subsequent fibre differentiation.
Related JoVE Video
Absence of intestinal PPAR? aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway.
PLoS Pathog.
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
To be able to colonize its host, invading Salmonella enterica serovar Typhimurium must disrupt and severely affect host-microbiome homeostasis. Here we report that S. Typhimurium induces acute infectious colitis by inhibiting peroxisome proliferator-activated receptor gamma (PPAR?) expression in intestinal epithelial cells. Interestingly, this PPAR? down-regulation by S. Typhimurium is independent of TLR-4 signaling but triggers a marked elevation of host innate immune response genes, including that encoding the antimicrobial peptide lipocalin-2 (Lcn2). Accumulation of Lcn2 stabilizes the metalloproteinase MMP-9 via extracellular binding, which further aggravates the colitis. Remarkably, when exposed to S. Typhimurium, Lcn2-null mice exhibited a drastic reduction of the colitis and remained protected even at later stages of infection. Our data suggest a mechanism in which S. Typhimurium hijacks the control of host immune response genes such as those encoding PPAR? and Lcn2 to acquire residence in a host, which by evolution has established a symbiotic relation with its microbiome community to prevent pathogen invasion.
Related JoVE Video
Role of sunitinib and SU12662 on dermatological toxicities in metastatic renal cell carcinoma patients: in vitro, in vivo, and outcomes investigation.
Cancer Chemother. Pharmacol.
PUBLISHED: 06-19-2013
Show Abstract
Hide Abstract
Sunitinib commonly exhibits dose-limiting dermatological toxicities (DTs) that adversely affect health-related quality of life (HRQoL). Pharmacological activity of sunitinib is attributed to sunitinib and an equipotent, active metabolite, SU12662. The objective of this study is to compare the dermatotoxic potential of sunitinib and SU12662, and changes in HRQoL due to DTs.
Related JoVE Video
Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus k
J. Med. Chem.
PUBLISHED: 12-29-2011
Show Abstract
Hide Abstract
Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
Related JoVE Video
Wnt signaling orchestration with a small molecule DYRK inhibitor provides long-term xeno-free human pluripotent cell expansion.
Stem Cells Transl Med
PUBLISHED: 12-07-2011
Show Abstract
Hide Abstract
An optimal culture system for human pluripotent stem cells should be fully defined and free of animal components. To date, most xeno-free culture systems require human feeder cells and/or highly complicated culture media that contain activators of the fibroblast growth factor (FGF) and transforming growth factor-? (TGF?) signaling pathways, and none provide for replacement of FGF/TGF? ligands with chemical compounds. The Wnt/?-catenin signaling pathway plays an important role in mouse embryonic stem cells in leukemia inhibitory factor-independent culture; however, the role of Wnt/?-catenin signaling in human pluripotent stem cell is still poorly understood and controversial because of the dual role of Wnts in proliferation and differentiation. Building on our previous investigations of small molecules modulating Wnt/?-catenin signaling in mouse embryonic stem cells, we identified a compound, ID-8, that could support Wnt-induced human embryonic stem cell proliferation and survival without differentiation. Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) is the target of the small molecule ID-8. Its role in human pluripotent cell renewal was confirmed by DYRK knockdown in human embryonic stem cells. Using Wnt and the DYRK inhibitor ID-8, we have developed a novel and simple chemically defined xeno-free culture system that allows for long-term expansion of human pluripotent stem cells without FGF or TGF? activation. These culture conditions do not include xenobiotic supplements, serum, serum replacement, or albumin. Using this culture system, we have shown that several human pluripotent cell lines maintained pluripotency (>20 passages) and a normal karyotype and still retained the ability to differentiate into derivatives of all three germ layers. This Wnt-dependent culture system should provide a platform for complete replacement of growth factors with chemical compounds.
Related JoVE Video
Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor
J. Med. Chem.
PUBLISHED: 06-15-2011
Show Abstract
Hide Abstract
Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.
Related JoVE Video
Acidic nuclear phosphoprotein 32kDa (ANP32)B-deficient mouse reveals a hierarchy of ANP32 importance in mammalian development.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 06-02-2011
Show Abstract
Hide Abstract
The highly conserved ANP32 proteins are proposed to function in a broad array of physiological activities through molecular mechanisms as diverse as phosphatase inhibition, chromatin regulation, caspase activation, and intracellular transport. On the basis of previous analyses of mice bearing targeted mutations of Anp32a or Anp32e, there has been speculation that all ANP32 proteins play redundant roles and are dispensable for normal development. However, more recent work has suggested that ANP32B may in fact have functions that are not shared by other ANP32 family members. Here we report that ANP32B expression is associated with a poor prognosis in human breast cancer, consistent with the increased levels of Anp32b mRNA present in proliferating wild-type (WT) murine embryonic fibroblasts and stimulated WT B and T lymphocytes. Moreover, we show that, contrary to previous assumptions, Anp32b is very important for murine embryogenesis. In a mixed genetic background, ANP32B-deficient mice displayed a partially penetrant perinatal lethality that became fully penetrant in a pure C57BL/6 background. Surviving ANP32B-deficient mice showed reduced viability due to variable defects in various organ systems. Study of compound mutants lacking ANP32A, ANP32B, and/or ANP32E revealed previously hidden roles for ANP32A in mouse development that became apparent only in the complete absence of ANP32B. Our data demonstrate a hierarchy of importance for the mammalian Anp32 genes, with Anp32b being the most critical for normal development.
Related JoVE Video
Cardiovascular changes during maturation and ageing in male and female spontaneously hypertensive rats.
J. Cardiovasc. Pharmacol.
PUBLISHED: 02-02-2011
Show Abstract
Hide Abstract
Cardiovascular remodeling leading to heart failure is common in the elderly. Testing effective pharmacological treatment of human heart failure requires a suitable animal model that adequately mimics the human disease state.
Related JoVE Video
The Wnt signaling pathway in cellular proliferation and differentiation: A tale of two coactivators.
Adv. Drug Deliv. Rev.
PUBLISHED: 07-14-2010
Show Abstract
Hide Abstract
Wnt signaling pathways play divergent roles during development, normal homeostasis and disease. The responses that result from the activation of the pathway control both proliferation and differentiation. Tight regulation and controlled coordination of the Wnt signaling cascade is required to maintain the balance between proliferation and differentiation. The non-redundant roles of the coactivator proteins CBP and p300, within the context of Wnt signaling are discussed. We highlight their roles as integrators of the various inputs that a cell receives to elicit the correct and coordinated response. We propose that essentially all cellular information - i.e. from other signaling pathways, nutrient levels, etc. - is funneled down into a choice of coactivators usage, either CBP or p300, by their interacting partner beta-catenin (or catenin-like molecules in the absence of beta-catenin) to make the critical decision to either remain quiescent, or once entering cycle to proliferate without differentiation or to initiate the differentiation process.
Related JoVE Video
Interrelations between plasma caffeine concentrations and neurobehavioural effects in healthy volunteers: model analysis using NONMEM.
Biopharm Drug Dispos
PUBLISHED: 06-26-2010
Show Abstract
Hide Abstract
The objective was to develop a population pharmacokinetic-pharmacodynamic model of caffeines psychomotor effects in healthy, non-habitual users of caffeine. Twenty Chinese males each received a single dose of 250 mg of caffeine orally. Plasma concentrations of caffeine were determined at various times within 24 h after dosing. The subjects psychomotor performance was evaluated before and at various times after dosing by a test battery consisting of oculomotor assessment (saccadic velocity) as well as the computerised Swedish Performance Evaluation System. Nonlinear mixed-effects modelling to analyse the pharmacokinetic-pharmacodynamic relationships was performed using NONMEM. Model robustness was assessed by a nonparametric bootstrap. The results showed that caffeine caused significant improvements in psychomotor functioning. The time course of these effects was best described by pharmacokinetic/pharmacodynamic models involving an effect compartment. The transfer half-lives between plasma and effect site for different domains of psychomotor functioning were in the range 24.8-49.5 min. Evaluation of the final models showed close agreement between pairs of bootstrapped and final model parameter estimates (all differences<10%). These results provided the first suggestive evidence that caffeine effects on psychomotor performance occur after some time delay relative to changes in plasma caffeine concentration. The models for the neurobehavioural tests provided similar transfer half-lives between plasma and effect site.
Related JoVE Video
Synthesis and evaluation of alkenyl indazoles as selective Aurora kinase inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 03-01-2010
Show Abstract
Hide Abstract
A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays.
Related JoVE Video
Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis.
Cancer Treat. Rev.
Show Abstract
Hide Abstract
Although existing evidence from clinical trials has demonstrated manifestation of hepatic adverse events (AEs) with the use of tyrosine kinase inhibitors (TKIs), overall risks have yet to be reported. Thus we conducted a meta-analysis to determine the risk of hepatotoxicity associated with the use of TKIs, by comparing the occurrence of hepatotoxicity of the TKI arms against that of comparison arms.
Related JoVE Video
Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3).
J Mol Model
Show Abstract
Hide Abstract
A high-throughput screen against Aurora A kinase revealed several promising submicromolar pyrimidine-aniline leads. The bioactive conformation found by docking these leads into the Aurora A ATP-binding site had a semicircular shape. Macrocycle formation was proposed to achieve novelty and selectivity via ring-closing metathesis of a diene precursor. The nature of the optimal linker and its size was directed by docking. In a kinase panel screen, selected macrocycles were active on other kinase targets, mainly FLT3, JAK2, and CDKs. These compounds then became leads in a CDK/FLT3/JAK2 inhibitor project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. Interaction with this residue explains the observed selectivity. The Asp86 residue is conserved in most CDKs, resulting in potent pan-CDK inhibition by these compounds. Optimized macrocycles generally have good DMPK properties, and are efficacious in mouse models of cancer. Compound 5 (SB1317/TG02), a pan-CDK/FLT3/JAK2 inhibitor, was selected for preclinical development, and is now in phase 1 clinical trials.
Related JoVE Video
Effect of CYP3A4 inducer dexamethasone on hepatotoxicity of lapatinib: clinical and in vitro evidence.
Breast Cancer Res. Treat.
Show Abstract
Hide Abstract
Concomitant usage of lapatinib, a cytochrome P450 (CYP) 3A4 substrate and dexamethasone, a CYP3A4 inducer, is a pharmacokinetic drug-drug interaction. This combination may increase the formation of reactive lapatinib metabolites, which is potentially hepatotoxic. This study aims to evaluate the clinical effect of dexamethasone on incidence of hepatotoxicity and to ascertain its in vitro role using a parallel cell culture model experimental setup. Clinical effects of dexamethasone on lapatinib-induced hepatotoxicity were evaluated in a nested case-control study based on 120 patient data obtained from our records. For the in vitro experiment, metabolically competent transforming growth factor ? mouse hepatocytes (TAMH) were treated with lapatinib and viabilities were compared in the presence or absence of dexamethasone. After adjusting for confounders, patients receiving the combination were 4.57 times (95% CI 1.23-16.88, p = 0.02) more likely to develop hepatotoxicity and 3.48 times (95% CI 1.24-9.80, p = 0.02) more likely to develop a clinically important change in alanine aminotransferase than compared to the other group. Treatment of TAMH cells with lapatinib and dexamethasone caused a further reduction in viability, as compared to treatment with lapatinib alone. At 5 ?M lapatinib, the introduction of dexamethasone 20 ?M produced a 59% decline in viability. This is the first study to document a clinically important interaction between lapatinib and dexamethasone, which associates with an increased occurrence of hepatotoxicity. The in vitro findings have provided substantiating evidence and insights on the role of dexamethasone in lapatinib-induced hepatotoxicity.
Related JoVE Video

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.

How does it work?

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.