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Find video protocols related to scientific articles indexed in Pubmed.
A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis.
Blood
PUBLISHED: 09-10-2014
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Bim contributes to resistance to various standard and novel agents. Here we demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bim(hi)) in most MM cell lines and primary CD138(+) MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bim(hi) cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/Bcl-xL, potently killed bortezomib-resistant cells. These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bim(hi) cells. In Bim(low) cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bim expression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737-induced apoptosis in bim(-/-) mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy.
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Inhibition of the MDM2 E3 Ligase induces apoptosis and autophagy in wild-type and mutant p53 models of multiple myeloma, and acts synergistically with ABT-737.
PLoS ONE
PUBLISHED: 09-02-2014
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Intracellular proteolytic pathways have been validated as rational targets in multiple myeloma with the approval of two proteasome inhibitors in this disease, and with the finding that immunomodulatory agents work through an E3 ubiquitin ligase containing Cereblon. Another E3 ligase that could be a rational target is the murine double minute (MDM) 2 protein, which plays a role in p53 turnover. A novel inhibitor of this complex, MI-63, was found to induce apoptosis in p53 wild-type myeloma models in association with activation of a p53-mediated cell death program. MI-63 overcame adhesion-mediated drug resistance, showed anti-tumor activity in vivo, enhanced the activity of bortezomib and lenalidomide, and also overcame lenalidomide resistance. In mutant p53 models, inhibition of MDM2 with MI-63 also activated apoptosis, albeit at higher concentrations, and this was associated with activation of autophagy. When MI-63 was combined with the BH3 mimetic ABT-737, enhanced activity was seen in both wild-type and mutant p53 models. Finally, this regimen showed efficacy against primary plasma cells from patients with newly diagnosed and relapsed/refractory myeloma. These findings support the translation of novel MDM2 inhibitors both alone, and in combination with other novel agents, to the clinic for patients with multiple myeloma.
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Dysfunction of thermoregulation contributes to the generation of hyperthermia-induced seizures.
Neurosci. Lett.
PUBLISHED: 08-27-2014
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Febrile seizures (FS) are generally defined as seizures taking place during fever. Long-term prognosis, including development of epilepsy and malformation of cognitive function, has been demonstrated after infantile FS. However, the mechanism that triggers seizures in hyperthermic environment is still unclear. We here found that the body temperature of rat pups that experienced experimental FS was markedly decreased (?28°C) after they were removed from the hyperthermic environment. Both the seizure generation and the temperature drop after seizure attack were abolished by either pre-treatment with chlorpromazine (CPZ), which impairs the thermoregulation, or by an electrolytic lesion of the preoptic area and anterior hypothalamus (PO/AH). However, the non-steroidal anti-inflammatory drug celecoxib did not affect the seizure incidence and the decrease in body temperature after seizure attack. In addition, pentobarbital prevented the generation of seizures, but did not reverse the decrease of body temperature after FS. Therefore, our work indicates that an over-regulation of body temperature occurs during hyperthermic environment, and that the dysfunction of thermoregulation in the PO/AH following hyperthermia contributes to the generation of FS.
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Embelin inhibits pancreatic cancer progression by directly inducing cancer cell apoptosis and indirectly restricting IL-6 associated inflammatory and immune suppressive cells.
Cancer Lett.
PUBLISHED: 08-13-2014
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Pancreatic cancer is an aggressive malignancy and unresponsive to conventional chemotherapies. Here, the anti-inflammatory and anti-tumor effects of embelin on pancreatic cancer were investigated. Embelin significantly attenuated cells invasion, proliferation and induced apoptosis through inhibition of STAT3 and activation of p53 signaling pathways. Embelin substantially reduced the tumorigenicity of pancreatic cancer cells in vivo, which was associated with reduced inflammatory cells and immune suppressive cells, IL-17A(+) Th17, GM-CSF(+) Th, MDSCs and Treg, through inhibition of IL-6 secretion. Moreover, embelin decrease IL-6-induced STAT3 phosphorylation. In summary, embelin represents a novel therapeutic drug candidate for the clinical treatment of pancreatic cancer.
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Targeting SQSTM1/p62 induces cargo loading failure and converts autophagy to apoptosis via NBK/Bik.
Mol. Cell. Biol.
PUBLISHED: 07-07-2014
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In selective autophagy, the adaptor protein SQSTM1/p62 plays a critical role in recognizing/loading cargo (e.g., malfolded proteins) into autophagosomes for lysosomal degradation. Here we report that whereas SQSTM1/p62 levels fluctuated in a time-dependent manner during autophagy, inhibition or knockdown of Cdk9/cyclin T1 transcriptionally downregulated SQSTM1/p62 but did not affect autophagic flux. These interventions, or short hairpin RNA (shRNA) directly targeting SQSTM1/p62, resulted in cargo loading failure and inefficient autophagy, phenomena recently described for Huntington's disease neurons. These events led to the accumulation of the BH3-only protein NBK/Bik on endoplasmic reticulum (ER) membranes, most likely by blocking loading and autophagic degradation of NBK/Bik, culminating in apoptosis. Whereas NBK/Bik upregulation was further enhanced by disruption of distal autophagic events (e.g., autophagosome maturation) by chloroquine (CQ) or Lamp2 shRNA, it was substantially diminished by inhibition of autophagy initiation (e.g., genetically by shRNA targeting Ulk1, beclin-1, or Atg5 or pharmacologically by 3-methyladenine [3-MA] or spautin-1), arguing that NBK/Bik accumulation stems from inefficient autophagy. Finally, NBK/Bik knockdown markedly attenuated apoptosis in vitro and in vivo. Together, these findings identify novel cross talk between autophagy and apoptosis, wherein targeting SQSTM1/p62 converts cytoprotective autophagy to an inefficient form due to cargo loading failure, leading to NBK/Bik accumulation, which triggers apoptosis.
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Contrast Sensitivity Function after Correcting Residual Wavefront Aberrations during RGP Lens Wear.
Optom Vis Sci
PUBLISHED: 04-29-2014
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To investigate the effect on the contrast sensitivity function (CSF) of correcting the residual wavefront aberrations in myopic and keratoconic subjects wearing rigid gas permeable (RGP) contact lenses.
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Molecular and cellular basis of the regulation of lymphatic contractility and lymphatic absorption.
Int. J. Biochem. Cell Biol.
PUBLISHED: 04-22-2014
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Lymphatic absorption is a highly regulated process driven by both an extrinsic mechanism (external force) and an intrinsic mechanism (lymphatic vessel contractility). The lymphatic muscle is a specialized smooth muscle with unique mechanical properties. To understand the molecular mechanism and relative contribution of smooth muscle contraction in lymphatic absorption, we analyzed mice with a smooth muscle-specific deletion of Mylk, a critical gene for smooth muscle contraction. Interestingly, the knockout mice were significantly resistant to anesthesia reagents. Upon injection in the feet with FITC-dextran, the mutant mice displayed a 2-fold delay of the absorption peak in the peripheral circulation. Examining the ear lymphatic vessels of the mutant mice revealed a reduction in the amount of fluid in the lumens of the lymphangions, suggesting an impairment of lymph formation. The Mylk-deficient lymphatic muscle exhibited a significant reduction of peristalsis and of myosin light chain phosphorylation in response to depolarization. We thus concluded that MLCK and myosin light chain phosphorylation are required for lymphatic vessel contraction. Lymphatic contractility is not an exclusive requirement for lymphatic absorption, and external force appears to be necessary for absorption.
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Frequency and evolution of thin-capped fibroatheromas in left main coronary artery as assessed by serial virtual histology intravascular ultrasound analysis.
J Invasive Cardiol
PUBLISHED: 04-11-2014
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The objective of the current study was to assess thin-capped fibroatheroma (TCFA) of the left main coronary artery (LMCA) and its changes after statin therapy.
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Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights.
Pharmacol. Ther.
PUBLISHED: 04-10-2014
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Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.
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Differential expression of microRNA in peripheral blood mononuclear cells as specific biomarker for major depressive disorder patients.
J Psychiatr Res
PUBLISHED: 04-04-2014
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Currently, diagnosis and treatment of major depressive disorder (MDD) are based on the patients' description of symptoms, mental status examinations, and clinical behavioral observations, which increases the chance of misdiagnosis. There is a serious need to find a practical biomarker for the proper diagnosis of MDD. This study aimed to explore the possibility of microRNA (miRNA) in peripheral blood mononuclear cells (PBMCs) as specific blood-based biomarker for MDD patients. By using an Affymetrix array that covers 723 human miRNAs, we identified 26 miRNAs with significant changes in expression in PBMCs of MDD patients. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis in a larger cohort of 81 MDD patients and 46 healthy controls confirmed that the expression levels of 5 miRNAs (miRNA-26b, miRNA-1972, miRNA-4485, miRNA-4498, and miRNA-4743) were up-regulated. By receiver operating characteristic (ROC) curve analysis, the combining area under the ROC curve (AUC) of these five miRNAs was 0.636 [95% confidence interval (CI): 0.58-0.90]. MiRNA target gene prediction and functional annotation analysis showed that there was a significant enrichment in several pathways associated with nervous system and brain functions, supporting the hypothesis that differentially-regulated miRNAs may be involved in mechanism underlying development of MDD. We conclude that altered expression of miRNAs in PMBCs might be involved in multiple stages of MDD pathogenesis, and thus might be able to serve as specific biomarker for diagnosis of MDD.
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Vitamin D and nifedipine in the treatment of Chinese patients with grades I-II essential hypertension: a randomized placebo-controlled trial.
Atherosclerosis
PUBLISHED: 03-28-2014
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Low vitamin D status has been shown to be associated with hypertension. We planned to research the effect of vitamin D and nifedipine in the treatment of patients with essential hypertension.
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Immature visual neural system in children reflected by contrast sensitivity with adaptive optics correction.
Sci Rep
PUBLISHED: 03-27-2014
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This study aimed to explore the neural development status of the visual system of children (around 8 years old) using contrast sensitivity. We achieved this by eliminating the influence of higher order aberrations (HOAs) with adaptive optics correction. We measured HOAs, modulation transfer functions (MTFs) and contrast sensitivity functions (CSFs) of six children and five adults with both corrected and uncorrected HOAs. We found that when HOAs were corrected, children and adults both showed improvements in MTF and CSF. However, the CSF of children was still lower than the adult level, indicating the difference in contrast sensitivity between groups cannot be explained by differences in optical factors. Further study showed that the difference between the groups also could not be explained by differences in non-visual factors. With these results we concluded that the neural systems underlying vision in children of around 8 years old are still immature in contrast sensitivity.
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Embelin reduces colitis-associated tumorigenesis through limiting IL-6/STAT3 signaling.
Mol. Cancer Ther.
PUBLISHED: 03-20-2014
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The interleukin-6 (IL-6)/STAT3 signaling regulates survival and proliferation of intestinal epithelial cells and plays an important role in the pathogenesis of inflammatory bowel disease and colorectal cancer. Embelin is a small molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP), with antioxidant, anti-inflammatory, and antitumor activities. We previously showed that embelin inhibits the growth of colon cancer cells in vitro, and effectively suppresses 1,2-dimethylhydrazine dihydrochloride-induced colon carcinogenesis in mice. Here, we explored the antitumor effects and mechanisms of embelin on colitis-associated cancer (CAC) using the azoxymethane/dextran sulfate sodium (AOM/DSS) model, with a particular focus on whether embelin exerts its effect through the IL-6/STAT3 pathway. We found that embelin significantly reduced incidence and tumor size in CAC-bearing mice. In addition to inhibiting proliferation of tumor epithelial cells, embelin suppressed colonic IL-6 expression and secretion, and subsequently STAT3 activation in vivo. Importantly, in vitro studies have revealed that in colon cancer cells, embelin diminished both the constitutive and IL-6-induced STAT3 activation by stimulating Src homology domain 2-containing protein tyrosine phosphatase (SHP2) activity. Moreover, embelin protected mice from AOM/DSS-induced colitis before tumor development. Embelin decreased IL-1?, IL-17a, and IL-23a expression as well as the number of CD4(+) T cells and macrophages infiltrating the colonic tissues. Thus, our findings demonstrated that embelin suppresses CAC tumorigenesis, and its antitumor effect is partly mediated by limiting IL-6/STAT3 activation and Th17 immune response. Embelin may be a potential agent in the prevention and treatment of CAC.
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Gender difference in acquired seizure susceptibility in adult rats after early complex febrile seizures.
Neurosci Bull
PUBLISHED: 03-11-2014
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Gender differences are involved in many neurological disorders including epilepsy. However, little is known about the effect of gender difference on the risk of epilepsy in adults with a specific early pathological state such as complex febrile seizures (FSs) in infancy. Here we used a well-established complex FS model in rats and showed that: (1) the susceptibility to seizures induced by hyperthermia, pentylenetetrazol (PTZ), and maximal electroshock (MES) was similar in male and female rat pups, while males were more susceptible to PTZ- and MES-induced seizures than age-matched females in normal adult rats; (2) adult rats with complex FSs in infancy acquired higher seizure susceptibility than normal rats; importantly, female FS rats were more susceptible to PTZ and MES than male FS rats; and (3) the protein expression of interleukin-1?, an inflammatory factor associated with seizure susceptibility, was higher in adult FS females than in males, which may reflect a gender-difference phenomenon of seizure susceptibility. Our results provide direct evidence that the acquired seizure susceptibility after complex FSs is gender-dependent.
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A preliminary analysis of association between the down-regulation of microRNA-181b expression and symptomatology improvement in schizophrenia patients before and after antipsychotic treatment.
J Psychiatr Res
PUBLISHED: 03-11-2014
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Despite the growing evidences on the relation of altered expression of miRNAs and schizophrenia, most schizophrenia subjects have an extensive antipsychotic treatment history and the pharmacological effects on miRNA expression are largely unknown. This study aimed to investigate the change of plasma microRNA-181b level and improvement of symptomatology before and after six-week antipsychotic treatment in schizophrenia patients, and explore their association. A total of 20 schizophrenia patients absent of antipsychotics and 20 age-and gender-matched normal controls were enrolled, and tested for 9 schizophrenia-associated microRNA (miR-30e, miR-34a, miR-181b, miR-195, miR-346, miR-432, miR-7, miR-132 and miR-212) expression levels in plasma using quantitative RT-PCR and for symptomatology improvement using Positive And Negative Syndrome Scale (PANSS) before and after treatment (olanzapine, quetiapine, ziprasidone and risperidone) for the patients only. Compared with the normal control group, the expression levels of miRNA-181b, miRNA-30e, miRNA-34a and miRNA-7 of the patients group were significantly higher (p < 0.05). Compared with those before treatment in the patient group, the symptomatology scores were significantly lower (p < 0.001), and the expression level of microRNA-181b was significantly down-regulated after treatment (p < 0.05). The change of miRNA-181b expression was positively correlated with the improvement of negative symptoms and lack of response symptoms (r = 0.502 and 0.557, P < 0.05, accounting for 20.2% and 26.4% respectively), and their therapeutic effects with OR being 11.283 and 5.119 respectively. We conclude that miRNA-181b, miRNA-30e, miRNA-34a and miRNA-7 are probably involved in pathogenesis of SZ, and the significant down-regulation of miRNA-181b expression predicts improvement of negative symptoms to treatment, and thus can serve as a potential plasmamolecular marker for antipsychotic responses.
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Esophageal Helicobacter pylori colonization aggravates esophageal injury caused by reflux.
World J. Gastroenterol.
PUBLISHED: 01-30-2014
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To investigate esophageal Helicobacter pylori (H. pylori) colonization on esophageal injury caused by reflux and the related mechanisms.
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Chromosomal aneuploidies and combinational fluorescence in situ hybridization probe panels are useful for predicting prognosis for esophageal squamous cell carcinoma.
J. Gastroenterol.
PUBLISHED: 01-23-2014
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Esophageal squamous cell carcinoma (ESCC) is a common cancer type in China. In this study, we aimed to develop aneuploidy markers for diagnosis and prognosis of ESCC.
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Vitamin d, parathyroid hormone, and serum lipid profiles in a middle-aged and elderly chinese population.
Endocr Pract
PUBLISHED: 01-23-2014
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Objectives: To explore the associations of serum vitamin D and parathyroid hormone (PTH) levels with serum lipid profiles and the risk of hyperlipidemia in a middle-aged and elderly population.Methods: A population-based cross-sectional study was conducted in the spring of 2012 among 1,203 Chinese participants, aged 52 to 101 years. 25-Hydroxyvitamin D [25(OH)D] was measured by chemiluminescence assay. (PTH) levels were measured with an electrochemiluminescence immunoassay (ECLIA) method.Results: A total of 1,203 participants, including 526 women (43.7%), were evaluated in 2012. The median concentrations of serum 25(OH)D and PTH for the entire group were 17.3 ng/mL and 38.3 pg/mL, respectively. Serum 25(OH)D and PTH levels were not independently associated with serum total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels in a multivariate adjusted linear regression analysis of 1,027 participants not receiving antihyperlipidemic treatment (P>.05). In logistic regression analyses, serum 25(OH)D and PTH levels were not associated with a risk of hyperlipidemia after adjustment for age, sex, heavy drinking, smoking, diabetes, obesity, family history of hyperlipidemia, body mass index (BMI), physical activity, glomerular filtration rate (GFR), fasting glucose, high-sensitivity C-reactive protein (hsCRP), calcium, and hemoglobin.Conclusions: Serum 25(OH)D and PTH levels are not independently associated with serum lipid levels or an increased risk of hyperlipidemia in a middle-aged and elderly Chinese population.
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Prognostic value of high-sensitivity cardiac troponin T in patients with endomyocardial-biopsy proven cardiac amyloidosis.
J Geriatr Cardiol
PUBLISHED: 01-22-2014
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To investigate prognostic predictors of long-term survival of patients with cardiac amyloidosis (CA), and to determine predictive value of high-sensitivity cardiac troponin T (hs-cTnT) in CA patients.
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Transduced protein transduction domain linked HSP27 protected LECs against UVB radiation-induced damage.
Exp. Eye Res.
PUBLISHED: 01-17-2014
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PTD-fusion protein technology was used to transduce heat shock protein 27 (HSP27), an anti-apoptotic protein, into human lens epithelial cells (HLECs) (SRA01/04). The protein transduction domain (PTD) of the 11-amino acid YGRKKRRQRRR was tagged at the N-terminus of HSP27. The fusion protein was purified from bacteria transformed with a pKYB-PTD-HSP27 construct. The HLECs were incubated with PTD-HSP27-FITC and the fluorescence inside HLECs was found by fluorescence microscopic examination. To test the ability of PTD-HSP27 to pass through the corneas, PTD-HSP27-FITC was dropped onto the conjunctival sacs of rabbits; fluorescent labeled PTD-HSP27 was then observed in the rabbit aqueous humor. After being incubated with the PTD-HSP27 protein and irradiated with ultraviolet-B (UVB) light, HLECs was analyzed by flow cytometry, Hoechst 33258 staining and measurement of the potential of the mitochondrial transmembrane. HLECs incubated with PTD-HSP27 had a lower apoptotic rate and a higher mitochondrial membrane potential than the control cells. PTD-HSP27 appears to be sufficient to protect HLECs against UVB-induced apoptosis.
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Thermosensitive injectable hydrogel enhances the antitumor effect of embelin in mouse hepatocellular carcinoma.
J Pharm Sci
PUBLISHED: 01-14-2014
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Embelin, an active ingredient of traditional herbal medicine, is used to treat many diseases such as cancer. However, embelin is hydrophobic and insoluble in water, which makes it unsuitable for in vivo applications. In this study, we constructed an embelin-loaded thermosensitive injectable hydrogel system that we named Embelin/PECT(gel) based on the amphiphilic triblock copolymer of poly (?-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly (ethylene glycol)-poly (?-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT). The cytotoxicity and the antitumor effects of Embelin/PECT(gel) on mouse hepatic cancers were investigated in vitro and in vivo. Results indicated that embelin was formulated in PECT hydrogel and could be continuously released from Embelin/PECT(gel) , showing a higher cytotoxicity for H22 cells in vitro compared with free embelin. The aqueous solution of Embelin/PECT(gel) transformed into gel at the injection site within seconds, which later eroded and degraded over time in vivo. A single local peritumoral injection of Embelin/PECT(gel) in liver at a low dosage of 0.5 mg per mouse exhibited a significant antitumor effect, which was comparable to the antitumor effect of the embelin solution treatment at a total dose of 6 mg per mouse in mouse hepatic cancer. Embelin/PECT(gel) , as a drug delivery system in liver, represents a novel therapeutic drug candidate for the clinical treatment of advanced hepatocellular carcinoma.
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The J-curve relationship between diastolic pressure and coronary collateral circulation in patients with single chronic total occlusion.
Atherosclerosis
PUBLISHED: 01-10-2014
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In our previous study, we had shown that high diastolic blood pressure (DBP) was positively related to well-developed coronary collateral circulation (CCC). This study sought to find out the more precise relationship between DBP and CCC.
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Safety and efficacy of intravenous esmolol before prospective electrocardiogram-triggered high-pitch spiral acquisition for computed tomography coronary angiography.
J Geriatr Cardiol
PUBLISHED: 01-04-2014
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In order to acquire a high quality image with a low radiation dose, prospective electrocardiogram (ECG)-triggered computed tomography coronary angiography (CTCA) requires a stable heart rate (HR) < 65 beats/min. Esmolol has the advantage of reducing HR. The objective of this article is to assess the value of intravenous esmolol treatment before prospective ECG-triggered high-pitch spiral acquisition for CTCA.
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Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.
PLoS ONE
PUBLISHED: 01-01-2014
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The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.
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[Association between genetic polymorphisms in pre-miR-146a and pre-miR-196a2 and genetic damage levels among coke oven workers].
Zhonghua Yu Fang Yi Xue Za Zhi
PUBLISHED: 11-20-2013
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To investigate the association of rs2910164 G > C polymorphism and rs11614913 T > C polymorphism in pre-miR-146a and pre-miR-196a2 with genetic damage levels in coke oven workers.
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Relation of Low Vitamin D to Nonvalvular Persistent Atrial Fibrillation in Chinese Patients.
Ann Noninvasive Electrocardiol
PUBLISHED: 11-08-2013
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Low vitamin D status has been associated with increased risk of cardiovascular disease. Atrial fibrillation (AF) is the most common cardiac arrhythmia. We evaluated the association between low vitamin D and AF.
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[Relevance between carotid plaque scores and the severity of coronary atherosclerosis].
Zhonghua Yi Xue Za Zhi
PUBLISHED: 10-16-2013
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To explore the relevance between carotid plaque and the severity of coronary artery disease.
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[Anticoagulant efficacy and safety of argatroban for patients undergoing elective percutaneous coronary intervention].
Zhonghua Xin Xue Guan Bing Za Zhi
PUBLISHED: 10-12-2013
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To investigate the anticoagulant efficacy and safety of argatroban for patients undergoing elective percutaneous coronary intervention (PCI).
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[DNA extraction and sex determination for human teeth dated 3000 years ago unearthed in Xian].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi
PUBLISHED: 10-01-2013
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To extracted DNA from ancient human teeth dated 3000 years ago unearthed in Xian and determine the genders for the individuals.
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Multifunctional Core-Shell Structured Nanocarriers for Synchronous Tumor Diagnosis and Treatment In Vivo.
Chem Asian J
PUBLISHED: 09-15-2013
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Multifunctional, mesoporous, silica-coated upconversion luminescent/magnetic NaGdF4 :Yb/Er@NaGdF4 :Yb@mSiO2 ?PEG (referred to as UCNPS; PEG=polyethylene glycol) nanocomposites were fabricated through a phase-transfer-assisted surfactant-templating coating process, followed by hydrophilic polymer (PEG) functionalization to improve the stability and biocompatibility. The UCNP core imparts the nanomaterials with luminescence and magnetic properties for simultaneous upconversion optical and magnetic resonance (MR) imaging, whereas the mesoporous shell affords the nanomaterials the ability to load the anticancer drug doxorubicin. Proof-of-principle in vitro and in vivo experiments are presented to demonstrate that the resultant composite nanomaterials can serve as nanotheranostics for synchronous upconversion luminescence/MR dual modal imaging and anticancer drug delivery; this finally realizes the integration of diagnostics and the treatment of cancers.
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[A preliminary study of the inhibitive efficacy of iodized linoleic acid and its fluorodeoxyuridine ester in hepatocellular cancer].
Zhonghua Gan Zang Bing Za Zhi
PUBLISHED: 09-13-2013
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To explore the potential of iodized linoleic acid (ILA) and its 5-fluoro-deoxyuridine ester (IFU) to inhibit hepatocellular carcinoma (HCC) cells in vitro and tumors in vivo.
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PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells.
Cancer Biol. Ther.
PUBLISHED: 08-07-2013
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The present studies examined viability and DNA damage levels in mammary carcinoma cells following PARP1 and CHK1 inhibitor drug combination exposure. PARP1 inhibitors [AZD2281 ; ABT888 ; NU1025 ; AG014699] interacted with CHK1 inhibitors [UCN-01 ; AZD7762 ; LY2603618] to kill mammary carcinoma cells. PARP1 and CHK1 inhibitors interacted to increase both single strand and double strand DNA breaks that correlated with increased ?H2AX phosphorylation. Treatment of cells with CHK1 inhibitors increased the phosphorylation of CHK1 and ERK1/2. Knock down of ATM suppressed the drug-induced increases in CHK1 and ERK1/2 phosphorylation and enhanced tumor cell killing by PARP1 and CHK1 inhibitors. Expression of dominant negative MEK1 enhanced drug-induced DNA damage whereas expression of activated MEK1 suppressed both the DNA damage response and tumor cell killing. Collectively our data demonstrate that PARP1 and CHK1 inhibitors interact to kill mammary carcinoma cells and that increased DNA damage is a surrogate marker for the response of cells to this drug combination.
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[The clinical value of combining multiple features of CT in discriminating between benign and malignant lung lesions].
Sichuan Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 08-01-2013
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To develop a set of combined criteria of multiple features of chest CT for discriminating between benign and malignant lung lesions.
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Risk of cardiac rupture after acute myocardial infarction is related to a risk of hemorrhage.
J Zhejiang Univ Sci B
PUBLISHED: 07-31-2013
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Although cardiac rupture (CR) is a fatal mechanical complication of acute myocardial infarction (AMI), to date no predictive model for CR has been described. CR has common pathological characteristics with major bleeding. We aimed to investigate the relationship between the risk factors of major bleeding and CR. A total of 10202 consecutive AMI patients were recruited, and mechanical complications occurred in 72 patients. AMI patients without CR were chosen as control group. Clinical characteristics including bleeding-related factors were compared between the groups. The incidences of free wall rupture (FWR), ventricular septal rupture (VSR), and papillary muscle rupture (PMR) were 0.39%, 0.21%, and 0.09%, respectively, and the hospital mortalities were 92.5%, 45.5%, and 10.0%, respectively. Female proportion and average age were significantly higher in the groups of FWR and VSR than in the control group (P<0.01); higher white blood cell count and lower hemoglobin were found in all CR groups (P<0.01). Compared to the control group, patients with CR were more likely to receive an administration of thrombolysis [26.39% vs. 13.19%, P<0.05], and were less likely to be treated with primary percutaneous coronary intervention (PCI) [41.67% vs. 81.60%, P<0.05]. The major bleeding scores (integer scores) of FWR, VSR, and PMR were (17.70±7.24), (21.91±8.33), and (18.60±7.88), respectively, and were significantly higher than that of the control group (11.72±7.71) (P<0.05). A regression analysis identified age, increased heart rate, anemia, higher white blood cell count, and thrombolysis as independent risk factors of CR, most of which were major bleeding-related factors. The patients with CR have a significantly higher risk of hemorrhage compared to the group without CR. Risk of CR after AMI is related to the risk of hemorrhage.
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[An initial study on the feasibility of diagnosing myocardial ischemia with CT first-pass myocardial perfusion imaging at rest].
Zhonghua Xin Xue Guan Bing Za Zhi
PUBLISHED: 07-25-2013
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To assess the feasibility and accuracy of CT first-pass myocardial perfusion imaging (CT first-pass MPI) at rest for diagnosis of myocardial ischemia. Results of adenosine-induced myocardial perfusion scintigraphy (MPS) were used as gold standard.
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Translational research in oncology research & development and its impact on early development in China: report of the 5th Annual Meeting of the US Chinese Anti-Cancer Association (USCACA) at 2013 AACR Annual Meeting.
Chin J Cancer
PUBLISHED: 07-05-2013
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In April 2013, the US Chinese Anti-Cancer Association (USCACA) held its 5th annual meeting in conjunction with the American Association for Cancer Research (AACR) 2013 Annual Meeting in Washington DC. The USCACA executive committee reported activities and programs and highlighted the partnership and collaboration between USCACA and other major organizations. The key initiatives and programs of USCACA included 1) USCACA-TIGM Esophageal Cancer Program that funds translational research of esophageal cancer prevention and treatment at the Xinxiang Medical University in Henan province, China; 2) the USCACA-NFCR-AFCR Scholarship Program, which has supported 10 young outstanding Chinese cancer researchers and will award 4 fellowships at the Guangzhou International Symposium on Oncology in November this year; 3) USCACA-Hengrui Training Program for Early Phase Clinical Research, which has supported the training of a Chinese scholar at two major cancer centers in the US; and 4) USCACA has continued its partnership with the Chinese Journal of Cancer, which has reached significant international impact.
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Evaluation of neointimal coverage in patients with coronary artery aneurysm formation after drug-eluting stent implantation by optical coherence tomography.
Chin. Med. J.
PUBLISHED: 06-18-2013
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The vessel healing in patients with coronary artery aneurysms (CAA) that form after drug-eluting stent (DES) implantation is not clear. This study aims to assess the vessel healing in patients with CAA formation after DES implanation.
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[Pseudoaccommodation with accommodating intraocular lens in patients at different ages].
Zhonghua Yan Ke Za Zhi
PUBLISHED: 05-30-2013
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To compare the clinical performances of patients in different ages with implantation of a accommodating IOLs.
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Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway.
Biochem. Biophys. Res. Commun.
PUBLISHED: 05-03-2013
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Resveratrol (RSV) is a natural compound found in grapes and red wine. It has been well known for its beneficial effects as a dietary supplement in prevention of cardiovascular diseases and cancer. Recently, in vitro studies have reported the neuroprotective role of RSV in neurodegenerative process in Alzheimers disease (AD). However, in vivo effects of RSV on the decline of brain function accompanying the aging process, especially those on cognitive loss, have not been not investigated. Here we report that, after intraventricular injection of RSV for one week in 8-9 month-old mice, the long-term memory formation and the LTP induction from hippocampus CA1 were improved. The RSV enhancement effects were blocked in SIRT1 mutant mice. Additional experiments suggest that RSV effects are likely to be mediated through reduced expressions of miR-134 and miR-124, which may in turn up-regulate CREB levels to subsequently promote BDNF synthesis. These findings demonstrate a role for RSV in cognition and a microRNA-CREB-BDNF mechanism by which RSV regulates these processes, demonstrating its value as a potential therapeutic target against CNS disorders in aging.
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Supplementation of the maternal diet during pregnancy with chocolate and fructose interacts with the high-fat diet of the young to facilitate the onset of metabolic disorders in rat offspring.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 04-28-2013
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Obesity and non-alcoholic fatty liver disease are the most common metabolic disorders in society today. Previously, we found that supplementing the maternal diet during pregnancy with chocolate and fructose has negative effects on the well-being of the offspring that were ameliorated if the offspring were fed a normal diet during postnatal life. In the present study, we investigated whether feeding offspring a high-fat diet would augment the maternal programming effects and whether extra protein supply can correct the low birth weight resulting from the chocolate-supplemented maternal diet. Pregnant Sprague-Dawley rats were divided into three groups and fed either standard chow (normal nutrition; NN), chocolate- and fructose-supplemented standard chow with casein sodium (overnutrition; ON) or the supplemented standard chow without casein sodium (malnutrition; MN) throughout pregnancy. Male offspring were weaned on either standard or high-fat chow. Dams in the MN group exhibited moderate weight gain, consumed 50% less protein (P < 0.001) but more carbohydrates during gestation and delivered pups with a 12% lower birth weight (P < 0.05) than pups in the NN group, results that are consistent with previous findings. When fed on a high-fat diet after birth, pups from dams in the MN group (MNHD) had 30% more body fat (P = 0.023) and liver triglyceride (TG) levels that were double (P < 0.01) those in offspring in the other groups, leading to fatty livers in these offspring at 14 weeks of age. Hepatic expression of the PPAR?, ApoB100, MTTP, CPT1 and SREBP1c genes was significantly downregulated in the MNHD group (P < 0.05 for all), indicating changes in lipid metabolism. Although dams in the ON group exhibited marked gestational weight gain (P < 0.01), they gave birth to normal weight pups that only manifested mild increases in body fat and liver TG content (P < 0.05), without significant changes in the expression of most genes when fed with the high-fat diet. The results suggest that the extra protein supply in the form of casein sodium was able to correct some negative programming effects of the chocolate and fructose supplementation of the maternal diet, which, in conjunction with a high-fat diet in the offspring, may facilitate the onset of metabolic disorders, with impaired liver gene expression possibly a key contributor.
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[Effects of the diet ratio of polyunsaturated fatty acids ?-3/?-6 on experimental colitis in mice].
Beijing Da Xue Xue Bao
PUBLISHED: 04-18-2013
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To investigate the effect of changed ratio of polyunsaturated fatty acids (PUFA) on dextran sulfate sodium (DSS)-induced colitis in mice.
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[The prospective register study of domestic tirofiban for clinical application in acute coronary syndrome].
Zhonghua Nei Ke Za Zhi
PUBLISHED: 04-16-2013
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To evaluate the current clinical application of domestic tirofiban in patients with acute coronary syndrome (ACS) and to explore its safety profile focused on the common causes and correlation factors for the hemorrhagic events.
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Regulation of the osteoblastic and chondrocytic differentiation of stem cells by the extracellular matrix and subsequent bone formation modes.
Biomaterials
PUBLISHED: 03-27-2013
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While various factors have been reported to direct stem cell differentiation lineage, little is known about how nature orchestrates the mesenchymal stem cell (MSC) differentiation and bone morphogenesis during skeleton development and bone regeneration. The present study reports that the matrix has a critical regulating effect on MSC differentiation and the subsequent bone formation modes. A simply combined hydroxyapatite (HA)-collagen matrix stimulates the MSC differentiation into the osteoblastic lineage and leads to a straightforward intramembranous bone formation mode, in contrast to the chondrocytic differentiation and endochondral mode observed on HA-synthetic hydrogel matrix. The accelerated MSC condensation and robust MSC-matrix and MSC-MSC interactions on collagen-based matrix might be the critical factors contributing to such events, likely through the orchestrated signal cascades and cellular events modulated by the extracellular matrix. The results demonstrate that matrix plays critical role in modulating the stem cell differentiation lineage and bone formation mode, which has been largely overlooked.
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The novel Chk1 inhibitor MK-8776 sensitizes human leukemia cells to HDAC inhibitors by targeting the intra-S checkpoint and DNA replication and repair.
Mol. Cancer Ther.
PUBLISHED: 03-27-2013
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Interactions between the novel Chk1 inhibitor MK-8776 and the histone deacetylase (HDAC) inhibitor (HDACI) vorinostat were examined in human leukemia cells harboring wild-type (wt) or deficient p53. MK-8776 synergistically potentiated vorinostat-mediated apoptosis in various p53-wt or -deficient leukemia cell lines, whereas p53 knockdown by short hairpin RNA (shRNA) sensitized p53-wt cells to lethality of this regimen. Leukemia cell lines carrying FLT3-ITD were also sensitive to the MK-8776/vorinostat regimen. Synergistic interactions were associated with inhibition of Chk1 activity, interference with the intra-S-phase checkpoint, disruption of DNA replication, and downregulation of proteins involved in DNA replication (e.g., Cdt1) and repair (e.g., CtIP and BRCA1), resulting in sharp increases in DNA damage, reflected by enhanced ?-H2A.X formation, and apoptosis. Moreover, leukemia cells expressing kinase-dead Chk1 (D130A) or Chk1 shRNA were significantly more sensitive to HDACIs compared with their wt counterparts and displayed downregulation of CtIP and BRCA1 phosphorylation following HDACI exposure. Finally, the MK-8776/vorinostat regimen was active in primary acute myelogenous leukemia (AML) blasts, particularly against the CD34(+)/CD38(-)/CD123(+) population enriched for leukemia-initiating cells. In contrast, identical regimens were relatively sparing toward normal cord blood CD34(+) cells. Together, these findings indicate that the novel Chk1 inhibitor MK-8776 markedly potentiates HDACI lethality in leukemia cells displaying various genetic backgrounds through mechanisms involving disruption of the intra-S checkpoint, DNA replication, and DNA repair. They also argue that leukemic cells, including those bearing oncogenic mutations associated with poor prognosis, for example, p53 deletion/mutation or FLT3-ITD, may also be susceptible to this strategy.
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Thrombosis and morphology of plaque rupture using optical coherence tomography.
Chin. Med. J.
PUBLISHED: 03-20-2013
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Thrombosis following plaque rupture is the main cause of acute coronary syndrome, but not all plaque ruptures lead to thrombosis. There are limited in vivo data on the relationship between the morphology of ruptured plaque and thrombosis.
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Development and validation of a clinical risk score predicting the no-reflow phenomenon in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.
Cardiology
PUBLISHED: 03-08-2013
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The no-reflow phenomenon after a primary percutaneous coronary intervention (pPCI) in patients with acute ST-segment elevation myocardial infarction (STEMI) is a strong predictor of both short- and long-term mortality. We therefore developed and prospectively validated a risk score system in order to identify STEMI patients at high risk in terms of no-reflow after primary PCI.
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Computed tomography coronary angiography with a consistent dose below 2 mSv using double prospectively ECG-triggered high-pitch spiral acquisition in patients with atrial fibrillation: initial experience.
Int J Cardiovasc Imaging
PUBLISHED: 03-01-2013
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To evaluate the feasibility and imaging quality of double prospectively ECG-triggered high-pitch spiral acquisition mode (double flash mode) for coronary computed tomography angiography (CTCA) in patients with atrial fibrillation (AF). 47 patients (11 women, 36 men; mean age 64.5 ± 12.1 years) were enrolled for CTCA examinations using a dual-source CT with 2 × 128 × 0.6 mm collimation, 0.28 s rotation time and a pitch of 3.4. Double flash mode was prospectively triggered first at 60 % and later at 30 % of the R-R interval within two cardiac cycles. Image quality was evaluated using a four-point scale (1 = excellent, 4 = non-assessable). From 672 coronary artery segments, 77.5 % (521/672) was rated as score of 1, 20.8 % (140/672) as score of 2, 1.2 % (8/672) as score of 3 and 0.4 % (3/672) was rated as non-assessable. The average image quality score was 1.25 ± 0.38 on a per segment basis. Mean dose-length product for CTCA was 92.6 ± 28.2 mGy cm, the effective dose was 1.30 ± 0.39 mSv (0.64-1.97 mSv). In patients with AF, double prospectively ECG-triggered high-pitch spiral acquisition mode could be a feasible and valuable scan mode for CTCA with a consistent dose below 2 mSv as well as diagnostic imaging quality.
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The Effects of Low Vitamin D on Coronary Artery Disease.
Heart Lung Circ
PUBLISHED: 02-28-2013
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Coronary Artery Disease (CAD) remains a major cause of morbidity and mortality in the world. Low vitamin D status has been shown to be associated with increased risk of developing cardiovascular disease, hypertension and obesity. We planned to research the association between low vitamin D status and the severity of CAD.
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Hemolytic anemia case caused by an inverted inner felt after bentall operation.
J. Korean Med. Sci.
PUBLISHED: 02-26-2013
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A 26-yr-old male patient reported worsened dyspnea, dizziness one year after an emergency Bentall operation for type A aortic dissection. There was evidence of hemolytic anemia and aortogram revealed a significant stenosis at the distal anastomosis site. During the reoperation, we found the inner felt at the distal anastomosis was inverted causing a significant stenosis. The reoperation successfully resolved this problem. Here, we report a rare case of hemolytic anemia caused by an inverted inner felt after Bentall operation.
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The relationship between diastolic pressure and coronary collateral circulation in patients with stable angina pectoris and chronic total occlusion.
Am. J. Hypertens.
PUBLISHED: 02-07-2013
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The most important biomechanical source of activation of the coronary collateral circulation (CCC) is increased tangential fluid shear stress at the arterial endothelial surface. The coronary circulation is unique in that most coronary blood flow occurs in diastole. Consequently, the diastolic blood pressure (DBP) may influence the tangential fluid shear stress on the arterial endothelial surface in diastole, therebyaffecting development of the CCC.
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p.N78S and p.R161Q germline mutations of the VHL gene are present in von Hippel-Lindau syndrome in two pedigrees.
Mol Med Rep
PUBLISHED: 02-04-2013
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Von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome. VHL is characterized by the development of renal cell carcinoma (RCC), hemangioblastomas of the central nervous system or retina and pheochromocytoma (PCC). RCC and PCC are known to be caused by germline mutations of six and ten genes, respectively. In the present study, 30 individuals from two unrelated pedigrees with type 2A and 2C VHL syndrome were investigated. The patients were clinically examined and treated by radical nephrectomy [or nephron?sparing surgery (NSS)] and cortical-sparing adrenalectomy (CSA), and all members of the two families underwent genetic screening. Two members from the first family were diagnosed with PCC and RCC, and three individuals from the second family who had only hypertension were diagnosed with PCC. Heterozygous variants of the VHL gene, c.A233G (p.N78S) within exon 1 and c.G482A (p.R161Q) within exon 3, were verified, respectively. Surgery was performed on all the patients, with the exception of an asymptomatic 5-year-old p.N78S male in family 1, in addition to genetic testing and genetic counseling. Further patient follow-up was warranted with regard to blood pressure and health, although normal blood pressure and no local recurrence and distant metastasis of VHL were observed previously. The present study suggests that molecular genetic testing may aid the diagnosis and clinical management of VHL syndrome.
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Prevalence of coronary artery ectasia in older adults and the relationship with epicardial fat volume by cardiac computed tomography angiography.
J Geriatr Cardiol
PUBLISHED: 01-31-2013
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Coronary artery ectasia (CAE) refers to abnormal dilation of coronary artery segments to 1.5 times of adjacent normal ones. Epicardial fat is associated with cardiovascular risk factors. The relationship between CAE and epicardial fat has not yet been investigated. This study aimed to assess the relationship between CAE and epicardial fat volume (EFV) in older people by dual-source computed tomography coronary angiography (CTCA).
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A family of single-isomer, dicationic cyclodextrin chiral selectors for capillary electrophoresis: mono-6(A)-ammonium-6(C)-butylimidazolium-?-cyclodextrin chlorides.
Electrophoresis
PUBLISHED: 01-22-2013
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The first member of the single-isomer, dicationic cyclodextrin (CD) family, 6(A)-ammonium-6(C)-butylimidazolium-?-cyclodextrin chlorides (AMBIMCD), has been synthesized, analytically characterized, and used to separate a variety of acidic enantiomers and amino acids by CE. Starting from mono-6(A)-azido-?-cyclodextrin, the cationic imidazolium and ammonium moieties were subsequently introduced onto primary ring of ?-cyclodextrin via nucleophilic addition and Staudinger reaction. The analytically pure AC regio-isomer CD was further obtained via column chromatography. This dicationic CD exhibited excellent enantioselectivities for selected analytes at concentration as low as 0.5 mM, which were even better than those of its mono-imidazolium or ammonium-substitued counterpart CDs at 10 equivalent concentrations. The effective mobilities of all studied analytes were found to decrease with the concentration of AMBIMCD. Inclusion complexation in combination with eletrostatic interactions seemed to account for the enhanced chiral discrimination process.
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Let-7b is involved in the inflammation and immune responses associated with Helicobacter pylori infection by targeting Toll-like receptor 4.
PLoS ONE
PUBLISHED: 01-14-2013
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Toll-like receptors (TLRs) are important initiators in native immune responses to microbial infections. TLR4 is up-regulated in response to H.pylori infection in gastric epithelial cells. However, the regulatory mechanisms for the expression of TLR4 in H.pylori infection have not been clearly defined. The aims of this study are to present the evidence that microRNA let-7b directly regulates TLR4 expression in human gastric epithelial cells, and subsequently influences the activation of NF-?B and the expression of the downstream genes in H.pylori infection.
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Analysis of epigenetic changes in survivors of preterm birth reveals the effect of gestational age and evidence for a long term legacy.
Genome Med
PUBLISHED: 01-01-2013
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Preterm birth confers a high risk of adverse long-term health outcomes for survivors, yet the underlying molecular mechanisms are unclear. We hypothesized that effects of preterm birth can be mediated through measurable epigenomic changes throughout development. We therefore used a longitudinal birth cohort to measure the epigenetic mark of DNA methylation at birth and 18 years comparing survivors of extremely preterm birth with infants born at term.
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[Evaluation of neointimal proliferation in stented canine coronary artery with optical coherence tomography].
Nan Fang Yi Ke Da Xue Xue Bao
PUBLISHED: 12-01-2011
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To evaluate the accuracy of optical coherence tomography (OCT) in evaluating neointimal proliferation in canine coronary artery following stenting.
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Coronary plaque response after drug eluting stent implantation assessed by serial optical coherence tomography analysis.
Chin. Med. J.
PUBLISHED: 11-16-2011
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In general, percutaneous coronary intervention (PCI) relieves vessel stenosis by implantation of a stent, however, the relationship between plaque characteristics and response after stenting is not clear.
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Milk consumption and bladder cancer risk: a meta-analysis of published epidemiological studies.
Nutr Cancer
PUBLISHED: 11-01-2011
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Studies investigating the association of milk consumption with bladder cancer risk have reported inconsistent findings. We conducted a meta-analysis of published cohort and case-control studies to pool the risk estimates of the association between milk intake and bladder cancer. We quantified associations with bladder cancer using meta-analysis of odds ratio (OR) associated with the highest vs. the lowest category of milk intake using fixed- or random-effect models depending on the heterogeneity of effects among studies. Nineteen cohort and case-control studies were eligible for inclusion. High milk intake was significantly associated with decreased risk of bladder cancer (OR, 0.84; 95% CI, 0.71-0.97) when comparing the highest with the lowest category of milk intake. The inverse association was stronger in Asia (OR, 0.60; 95% CI, 0.40-0.81) than North America (OR, 0.89; 95% CI, 0.76-1.03), and no association was observed in Europe (OR, 1.05; 95% CI, 0.85-1.26). This relationship also varied significantly by specific dairy products. Our results suggest that milk may be related to the reduction of bladder cancer risk. Further studies need to clarify the biological mechanisms.
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Tissue factor/activated factor VIIa induces matrix metalloproteinase-7 expression through activation of c-Fos via ERK1/2 and p38 MAPK signaling pathways in human colon cancer cell.
Int J Colorectal Dis
PUBLISHED: 10-20-2011
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Increased expression of tissue factor (TF) is associated with tumor invasion and metastasis in human colorectal cancer. We have previously observed that TF/FVIIa upregulates matrix metalloproteinase-7 (MMP-7) expression at the transcriptional level in colon cancer cells. MMP-7 overexpression is believed to play an important role in tumor invasion and metastasis. The aim of this study is to elucidate the molecular mechanisms by which TF/FVIIa induced MMP-7 expression and cell invasion in vitro.
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Relationship between coronary artery plaque composition by virtual histology intravascular ultrasound analysis and brachial-ankle pulse wave velocity in patients with coronary artery disease.
Coron. Artery Dis.
PUBLISHED: 09-28-2011
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Brachial-ankle pulse wave velocity (baPWV) is an indicator of atherosclerotic cardiovascular risks. To identify patients with coronary atherosclerosis before the onset of angina pectoris or myocardial infarction will be desirable.
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A novel lignan glycoside with antioxidant activity from Tinospora sagittata var. yunnanensis.
Nat. Prod. Res.
PUBLISHED: 09-26-2011
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A novel lignan glysocide, namely sagitiside A (1), together with two known ones, (+)-lyoniresinol-2?-O-?-D-glucopyranoside (2) and (+)-5-methoxyisolariciresinol 3?-O-?-D-glucopyranoside (3), was isolated from the 95% ethanol extract of dry roots of Tinospora sagittata var. yunnanensis. The structure of the new compound (1) was determined based on MS, 1D and 2D NMR spectral data. Compounds 1-3 showed antioxidant activity with EC(50) values 55, 75 and 80 µM by 1,1-diphenyl-2-picryhydrazyl (DPPH) radical-scavenging assay.
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[Analysis of patients with extraction of open-loop anterior chamber intraocular lenses].
Zhonghua Yan Ke Za Zhi
PUBLISHED: 09-15-2011
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To analyze the cause of flexible open-loop anterior chamber intraocular lenses (AC-IOL) extraction and to evaluate the safety of these lenses implantation.
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Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2.
Blood
PUBLISHED: 09-12-2011
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Effects of Chk1 and MEK1/2 inhibition were investigated in cytokinetically quiescent multiple myeloma (MM) and primary CD138(+) cells. Coexposure to the Chk1 and MEK1/2 inhibitors AZD7762 and selumetinib (AZD6244) robustly induced apoptosis in various MM cells and CD138(+) primary samples, but spared normal CD138(-) and CD34(+) cells. Furthermore, Chk1/MEK1/2 inhibitor treatment of asynchronized cells induced G(0)/G(1) arrest and increased apoptosis in all cell-cycle phases, including G(0)/G(1). To determine whether this regimen is active against quiescent G(0)/G(1) MM cells, cells were cultured in low-serum medium to enrich the G(0)/G(1) population. G(0)/G(1)-enriched cells exhibited diminished sensitivity to conventional agents (eg, Taxol and VP-16) but significantly increased susceptibility to Chk1 ± MEK1/2 inhibitors or Chk1 shRNA knock-down. These events were associated with increased ?H2A.X expression/foci formation and Bim up-regulation, whereas Bim shRNA knock-down markedly attenuated lethality. Immunofluorescent analysis of G(0)/G(1)-enriched or primary MM cells demonstrated colocalization of activated caspase-3 and the quiescent (G(0)) marker statin, a nuclear envelope protein. Finally, Chk1/MEK1/2 inhibition increased cell death in the Hoechst-positive (Hst(+)), low pyronin Y (PY)-staining (2N Hst(+)/PY(-)) G(0) population and in sorted small side-population (SSP) MM cells. These findings provide evidence that cytokinetically quiescent MM cells are highly susceptible to simultaneous Chk1 and MEK1/2 inhibition.
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[Clinical manifestations of 43 patients with acute myocardial infarction complicated by free wall rupture].
Zhonghua Xin Xue Guan Bing Za Zhi
PUBLISHED: 09-09-2011
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To analyze the clinical characteristics of patients with acute myocardial infarction (AMI) complicated by free wall rupture (FWR) and to define the independent risk factors for FWR.
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Methods to study cancer therapeutic drugs that target cell cycle checkpoints.
Methods Mol. Biol.
PUBLISHED: 08-27-2011
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Cell cycle checkpoints operating through a network of multiple signaling pathways provide a key mechanism for self-defense of cells against DNA damage caused by various endogenous or environmental stresses. In cancer treatment, checkpoints are activated in response to diverse DNA-damaging agents and radiation, thus representing a critical barrier limiting therapeutic efficacy. To date, despite efforts to target other components of checkpoint signaling pathways (e.g., ATM, Chk2, Wee1), checkpoint kinase 1 (Chk1) remains the most important target for cancer treatment because of its functional association with essentially all cell cycle checkpoints. The primary goal in the development of therapeutic agents targeting cell cycle checkpoints continues to be improving the anti-cancer activity of chemo- and radiotherapy by abrogating checkpoints necessary for DNA repair, thereby killing cancer cells through engagement of the apoptotic machinery.
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The role of Tyk2 in regulation of breast cancer growth.
J. Interferon Cytokine Res.
PUBLISHED: 08-24-2011
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The antigrowth and immunomodulatory actions of interferons (IFNs) have enabled these cytokines to be used therapeutically for the treatment of a variety of hematologic and solid malignancies. IFNs exert their effects by activation of the Jak/Stat signaling pathway. IFN? stimulates the tyrosine kinases Jak1 and Jak2, resulting in activation of the Stat1 transcription factor, whereas type 1 IFNs (IFN?/?) activate Jak1 and Tyk2, which mediate their effects through Stat1 and Stat2. Disruption in the expression of IFN?, IFN? receptors, or Stat1 inhibits antitumor responses and blunt cancer immunosurveillance in mice. Mutations in Jak2 or constitutive activation of Jak1 or Jak2 also promote the development of a variety of malignancies. Although there are data indicating that Tyk2 plays a role in the pathogenesis of lymphomas, the effects of Tyk2 expression on tumorigenesis are unknown. We report here that Tyk2(-/-) mice inoculated with 4T1 breast cancer cells show enhanced tumor growth and metastasis compared to Tyk2(+/+) animals. Accelerated growth of 4T1?cells in Tyk2(-/-) animals does not appear to be due to decreased function of CD4(+), CD8(+) T cells, or NK cells. Rather, the tumor suppresive effects of Tyk2 are mediated at least in part by myeloid-derived suppressor cells, which appear to be more effective in inhibiting T cell responses in Tyk2(-/-) mice. Our results provide the first evidence for a role of Tyk2 in suppressing the growth and metastasis of breast cancer.
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Disruption of IkappaB kinase (IKK)-mediated RelA serine 536 phosphorylation sensitizes human multiple myeloma cells to histone deacetylase (HDAC) inhibitors.
J. Biol. Chem.
PUBLISHED: 08-04-2011
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Post-translational modifications of RelA play an important role in regulation of NF-?B activation. We previously demonstrated that in malignant hematopoietic cells, histone deacetylase inhibitors (HDACIs) induced RelA hyperacetylation and NF-?B activation, attenuating lethality. We now present evidence that I?B kinase (IKK) ?-mediated RelA Ser-536 phosphorylation plays a significant functional role in promoting RelA acetylation, inducing NF-?B activation, and limiting HDACI lethality in human multiple myeloma (MM) cells. Immunoblot profiling revealed that although basal RelA phosphorylation varied in MM cells, Ser-536 phosphorylation correlated with IKK activity. Exposure to the pan-HDACIs vorinostat or LBH-589 induced phosphorylation of IKK?/? (Ser-180/Ser-181) and RelA (Ser-536) in MM cells, including cells expressing an I?B? "super-repressor," accompanied by increased RelA nuclear translocation, acetylation, DNA binding, and transactivation activity. These events were substantially blocked by either pan-IKK or IKK?-selective inhibitors, resulting in marked apoptosis. Consistent with these events, inhibitory peptides targeting either the NF-?B essential modulator (NEMO) binding domain for IKK complex formation or RelA phosphorylation sites also significantly increased HDACI lethality. Moreover, IKK? knockdown by shRNA prevented Ser-536 phosphorylation and significantly enhanced HDACI susceptibility. Finally, introduction of a nonphosphorylatable RelA mutant S536A, which failed to undergo acetylation in response to HDACIs, impaired NF-?B activation and increased cell death. These findings indicate that HDACIs induce Ser-536 phosphorylation of the NF-?B subunit RelA through an IKK?-dependent mechanism, an action that is functionally involved in activation of the cytoprotective NF-?B signaling cascade primarily through facilitation of RelA acetylation rather than nuclear translocation.
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Simultaneous exposure of transformed cells to SRC family inhibitors and CHK1 inhibitors causes cell death.
Cancer Biol. Ther.
PUBLISHED: 08-01-2011
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The present studies were initiated to determine in greater molecular detail the regulation of CHK1 inhibitor lethality in transfected and infected breast cancer cells and using genetic models of transformed fibrobalsts. Multiple MEK1/2 inhibitors (PD184352, AZD6244 (ARRY-142886)) interacted with multiple CHK1 inhibitors (UCN-01 (7-hydroxystaurosporine), AZD7762) to kill mammary carcinoma cells and transformed fibroblasts. In transformed cells, CHK1 inhibitor -induced activation of ERK1/2 was dependent upon activation of SRC family non-receptor tyrosine kinases as judged by use of multiple SRC kinase inhibitors (PP2, Dasatinib; AZD0530), use of SRC/FYN/YES deleted transformed fibroblasts or by expression of dominant negative SRC. Cell killing by SRC family kinase inhibitors and CHK1 inhibitors was abolished in BAX/BAK -/- transformed fibroblasts and suppressed by over expression of BCL-XL. Treatment of cells with BCL-2/BCL-XL antagonists promoted SRC inhibitor + CHK1 inhibitor -induced lethality in a BAX/BAK-dependent fashion. Treatment of cells with [SRC + CHK1] inhibitors radio-sensitized tumor cells. These findings argue that multiple inhibitors of the SRC-RAS-MEK pathway interact with multiple CHK1 inhibitors to kill transformed cells.
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[Evaluation on the relationship between pregnancy associated plasma protein-a and intravascular ultrasound detected culprit coronary plaque morphology in patients with unstable angina].
Zhonghua Xin Xue Guan Bing Za Zhi
PUBLISHED: 07-26-2011
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To assess the relationship between pregnancy associated plasma protein-A (PAPP-A) and culprit coronary plaque morphology in patients with unstable angina (UA).
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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.