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Find video protocols related to scientific articles indexed in Pubmed.
Fluorescence correlation spectroscopy with visible-wavelength superconducting nanowire single-photon detector.
Opt Express
PUBLISHED: 11-18-2014
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We present the first demonstration of fluorescence correlation spectroscopy (FCS) using superconducting nanowire single-photon detectors (SSPDs) which are free of afterpulses unlike the avalanche photodiode (APD). Multimode-fiber-coupled SSPDs with high system detection efficiency for visible wavelengths were developed and implemented in the FCS system. We performed FCS measurements for Rhodamine B and 6G as fluorescent samples, and found that autocorrelation functions obtained by the SSPDs showed a noise-free curve in the short correlation time region of sub microseconds where the afterpulse effect was dominant using the APD. The obtained results clearly indicate the advantage of SSPDs for the FCS system.
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Multimode fiber-coupled superconducting nanowire single-photon detector with 70% system efficiency at visible wavelength.
Opt Express
PUBLISHED: 10-17-2014
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We report the development of the multimode fiber-coupled superconducting nanowire single-photon detector with high system detection efficiency at visible wavelength. The detector consists of a 10.5-nm-thick and 150-nm-wide NbN nanowire meander fabricated on a Si substrate with a multilayer dielectric mirror and a quarter wavelength cavity for obtaining high optical absorptance. The meander area was 35 µm in diameter and coupled with the GRIN-lensed multimode optical fiber with a core diameter of 50 µm. The system reached detection efficiency of 70% with dark count rate of 100 Hz at the wavelength of 635 nm, 3 dB roll-off response counting rate of 8.5 Mcps, and timing jitter of 76 ps.
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Hsa-miR-520d Converts Fibroblasts into CD105+ Populations.
Drugs R D
PUBLISHED: 10-12-2014
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We have previously shown that hsa-miR-520d-5p can convert cancer cells into induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs) via a dedifferentiation by a demethylation mechanism.
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Diagnostic benefits of adrenocortical scintigraphy in hepatic adrenal rest tumor.
Nihon Shokakibyo Gakkai Zasshi
PUBLISHED: 10-07-2014
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An 81-year-old female was referred to our hospital for the examination of an S7 liver tumor. The tumor was suspected to be a hepatic adrenal rest tumor (HART) based on ultrasonography, dynamic CT, Gd-EOB-DTPA-enhanced MRI, and CT during abdominal angiography. After various hormonal tests, the tumor was confirmed as hormonally non-functional. The diagnosis of HART was confirmed based on (131)I-adosterol accumulation in the tumor by adrenocortical scintigraphy. The resected tumor was histologically compatible with HART, and it may have been able to produce cortisol based on the immunohistochemical findings of various adrenocortical hormone metabolic enzymes. Adrenocortical scintigraphy may thus be useful in diagnosing HART.
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Drastic therapy for listerial brain abscess involving combined hyperbaric oxygen therapy and antimicrobial agents.
J Clin Neurol
PUBLISHED: 10-06-2014
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Listeria monocytogenes (L. monocytogenes) is a rare causative pathogen of brain abscess that is often found in immunocompromised patients. Although patients with supratentorial listerial abscesses showed a longer survival with surgical drainage, the standard therapy for patients with subtentorial lesions has not been established.
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Blood neutrophil to lymphocyte ratio as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy.
Hepatol. Res.
PUBLISHED: 09-01-2014
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Inflammation plays a critical role in cancer. The aim of the present study was to investigate the impact of neutrophil to lymphocyte ratio (NLR) on patients with advanced hepatocellular carcinoma (HCC) treated with hepatic arterial infusion chemotherapy (HAIC).
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[Familial amyloid polyneuropathy: liver transplantation as first-line therapy].
Brain Nerve
PUBLISHED: 07-08-2014
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Liver transplantation is the only potentially curative treatment currently available for transthyretin familial amyloid polyneuropathy (TTR-FAP) since transplantation results in the disappearance of amyloidogenic TTR, synthesized by the original liver, from plasma. An absolute risk reduction of 66.3%, class III evidence, and grade B recommendation demonstrate that liver transplantation prolongs survival in patients with FAP Val30Met. Effect of new therapeutic drugs should be compared with that of liver transplantation, and outcome improvement of therapy for FAP is expected.
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Molecular biology of liver cancer stem cells.
Liver Cancer
PUBLISHED: 06-20-2014
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Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. The concept of cancer stem cells (CSCs) is based primarily on the clinical and experimental observations that indicate the existence of a subpopulation of cells with the capacity to self-renew and differentiate as well as show increased resistance to radiation and chemotherapy. They are considered as the factors responsible for the cases of tumor relapse. Hepatic progenitor cells (HPCs) could form the basis of some hepatocellular carcinomas (HCC) and cholangiocarcinomas. Liver CSCs have been reported in multiple subtypes of HCC and are considered as the master regulators of HCC initiation, tumor metastasis, and progression. HPCs activators such as epithelial cell adhesion molecule (EpCAM), Wnt/?-catenin, transforming growth factor-beta (TGF-?), Notch and Hedgehog signaling systems expedite tumorigenesis or conversely, serve as a powerful cancer-prevention tool. Recent work has also identified Sal-like protein 4 (SALL4) and some epigenetic regulations as important molecules, while several therapeutic drugs that directly control HPCs have been tested both in vivo and in vitro. However, liver CSCs clearly have a complex pathogenesis, with the potential for considerable crosstalk and redundancy in signaling pathways. Hence, the targeting of single molecules or pathways may have limited benefit for treatment. In addition to the direct control of liver CSCs, many other factors are needed for CSC maintenance including angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance. Here, we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for their targeting.
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Concomitant accumulation of ?-synuclein and TDP-43 in a patient with corticobasal degeneration.
J. Neurol.
PUBLISHED: 06-18-2014
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Pathological changes in corticobasal degeneration (CBD) consist of abnormal deposition of the microtubule-associated protein tau. However, the simultaneous accumulation of different misfolded proteins in the brain can be observed in many neurodegenerative diseases with significantly longer disease durations. We encountered a patient with CBD who survived for an extremely long period (18 years) after the diagnosis. We performed an autopsy to elucidate the effect of the longer survival on the pathology of CBD. We observed abnormal aggregation of trans-activating response region DNA-binding protein of 43 kDa (TDP-43) and ?-synuclein, as well as phosphorylated tau, in neurons of broader regions of the brain, beyond the amygdala and other limbic areas. We found that phosphorylated tau, ?-synuclein, and TDP-43 partially co-existed in the same cellular aggregates. The triple pathologic changes might be related to the longer survival of the patient compared with the typical clinical course of patients with CBD. Further investigations are required to support the hypothesis that tauopathy, synucleinopathy, and TDP-43 proteinopathy might share common pathogenic mechanisms in terms of cross-seeding of the pathologic proteins.
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Frequency down-conversion of 637 nm light to the telecommunication band for non-classical light emitted from NV centers in diamond.
Opt Express
PUBLISHED: 06-13-2014
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We demonstrate a low-noise frequency down-conversion of photons at 637 nm to the telecommunication band at 1587 nm by the difference frequency generation in a periodically-poled lithium niobate. An internal conversion efficiency of the converter is estimated to be 0.44 at the maximum which is achieved by a pump power of 0.43 W, whereas a rate of internal background photons caused by the strong cw pump laser is estimated to be 9 kHz/mW within a bandwidth of about 1 nm. By using the experimental values related to the intrinsic property of the converter, and using the intensity correlation and the average photon number of a 637 nm input light pulse, we derive the intensity correlation of a converted telecom light pulse. Then we discuss feasibility of a single-photon frequency conversion to the telecommunication band for a long-distance quantum communication based on NV centers in diamond.
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Modified E91 protocol demonstration with hybrid entanglement photon source.
Opt Express
PUBLISHED: 06-13-2014
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We report on an experimental demonstration of the modified Ekert 91 protocol of quantum key distribution using a hybrid entanglement source with two different degrees of freedoms, a 1550 nm time-bin qubit and 810 nm polarization qubit. The violation of the Clauser-Horne-Shimony-Holt inequality could be demonstrated for the entanglement between the polarization qubit in free space and the time-bin qubit through 20 km fiber transmission. The secure key rate in our system is estimated 70-150 bps.
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Pulsed Sagnac polarization-entangled photon source with a PPKTP crystal at telecom wavelength.
Opt Express
PUBLISHED: 06-13-2014
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We demonstrate pulsed polarization-entangled photons generated from a periodically poled KTiOPO(4) (PPKTP) crystal in a Sagnac interferometer configuration at telecom wavelength. Since the group-velocity-matching (GVM) condition is satisfied, the intrinsic spectral purity of the photons is much higher than in the previous scheme at around 800 nm wavelength. The combination of a Sagnac interferometer and the GVM-PPKTP crystal makes our entangled source compact, stable, highly entangled, spectrally pure and ultra-bright. The photons were detected by two superconducting nanowire single photon detectors (SNSPDs) with detection efficiencies of 70% and 68% at dark counts of less than 1 kcps. We achieved fidelities of 0.981 ± 0.0002 for |?(-)? and 0.980 ± 0.001 for |?(+)? respectively. This GVM-PPKTP-Sagnac scheme is directly applicable to quantum communication experiments at telecom wavelength, especially in free space.
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A 64-pixel NbTiN superconducting nanowire single-photon detector array for spatially resolved photon detection.
Opt Express
PUBLISHED: 04-11-2014
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We present the characterization of two-dimensionally arranged 64-pixel NbTiN superconducting nanowire single-photon detector (SSPD) array for spatially resolved photon detection. NbTiN films deposited on thermally oxidized Si substrates enabled the high-yield production of high-quality SSPD pixels, and all 64 SSPD pixels showed uniform superconducting characteristics within the small range of 7.19-7.23 K of superconducting transition temperature and 15.8-17.8 ?A of superconducting switching current. Furthermore, all of the pixels showed single-photon sensitivity, and 60 of the 64 pixels showed a pulse generation probability higher than 90% after photon absorption. As a result of light irradiation from the single-mode optical fiber at different distances between the fiber tip and the active area, the variations of system detection efficiency (SDE) in each pixel showed reasonable Gaussian distribution to represent the spatial distributions of photon flux intensity.
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Orchestration of hepatocellular carcinoma development by diverse liver cancer stem cells.
J. Gastroenterol.
PUBLISHED: 03-09-2014
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Hepatocellular carcinoma (HCC) is one of the world's most aggressive diseases and carries a poor prognosis for patients. Recent evidence suggests that HCC is organized by cancer stem cells (CSCs), which are a subset of cells with stem cell-like features. CSCs are considered a pivotal target for the eradication of cancer, and liver CSCs have been investigated using various stem cell markers. Several hepatic stem/progenitor markers have been shown to be useful for isolating putative CSCs from HCC, although the expression patterns and phenotypic diversity of CSCs purified by these markers remain obscure. Recently, we found that liver CSCs defined by different markers show unique features of tumorigenicity and metastasis, with phenotypes closely associated with committed liver lineages. Furthermore, our data suggest that these distinct CSCs collaborate to orchestrate the tumorigenicity and metastasis of HCC. In this review article, we summarize the recent advances in understanding the pathogenesis and heterogeneity of liver CSCs.
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Gd-EOB-DTPA-enhanced magnetic resonance imaging and alpha-fetoprotein predict prognosis of early-stage hepatocellular carcinoma.
Hepatology
PUBLISHED: 02-20-2014
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The survival of patients with hepatocellular carcinoma (HCC) is often individually different even after surgery for early-stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) has been introduced recently to evaluate hepatic lesions with regard to vascularity and the activity of the organic anion transporter OATP1B3. Here we report that Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in combination with serum alpha-fetoprotein (AFP) status reflects the stem/maturational status of HCC with distinct biology and prognostic information. Gd-EOB-DTPA uptake in the hepatobiliary phase was observed in ?15% of HCCs. This uptake correlated with low serum AFP levels, maintenance of hepatocyte function with the up-regulation of OATP1B3 and HNF4A expression, and good prognosis. By contrast, HCC showing reduced Gd-EOB-DTPA uptake with high serum AFP levels was associated with poor prognosis and the activation of the oncogene FOXM1. Knockdown of HNF4A in HCC cells showing Gd-EOB-DTPA uptake resulted in the increased expression of AFP and FOXM1 and the loss of OATP1B3 expression accompanied by morphological changes, enhanced tumorigenesis, and loss of Gd-EOB-DTPA uptake in vivo. HCC classification based on EOB-MRI and serum AFP levels predicted overall survival in a single-institution cohort (n?=?70), and its prognostic utility was validated independently in a multi-institution cohort of early-stage HCCs (n?=?109).
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Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway.
Hepatology
PUBLISHED: 02-01-2014
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Malnutrition in the advanced fibrosis stage of chronic hepatitis C (CH-C) impairs interferon (IFN) signaling by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. However, the effect of profibrotic signaling on IFN signaling is not known. Here, the effect of transforming growth factor (TGF)-? signaling on IFN signaling and hepatitis C virus (HCV) replication was examined in Huh-7.5 cells by evaluating the expression of forkhead box O3A (Foxo3a), suppressor of cytokine signaling 3 (Socs3), c-Jun, activating transcription factor 2, ras homolog enriched in brain, and mTORC1. The findings were confirmed in liver tissue samples obtained from 91 patients who received pegylated-IFN and ribavirin combination therapy. TGF-? signaling was significantly up-regulated in the advanced fibrosis stage of CH-C. A significant positive correlation was observed between the expression of TGF-?2 and mothers against decapentaplegic homolog 2 (Smad2), Smad2 and Foxo3a, and Foxo3a and Socs3 in the liver of CH-C patients. In Huh-7.5 cells, TGF-?1 activated the Foxo3a promoter through an AP1 binding site; the transcription factor c-Jun was involved in this activation. Foxo3a activated the Socs3 promoter and increased HCV replication. TGF-?1 also inhibited mTORC1 and IFN signaling. Interestingly, c-Jun and TGF-? signaling was up-regulated in treatment-resistant IL28B minor genotype patients (TG/GG at rs8099917), especially in the early fibrosis stage. Branched chain amino acids or a TGF-? receptor inhibitor canceled these effects and showed an additive effect on the anti-HCV activity of direct-acting antiviral drugs (DAAs).
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Gait disturbance due to foot drop is refractory to treatment in nonsystemic vasculitic neuropathy.
Eur. Neurol.
PUBLISHED: 01-21-2014
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Nonsystemic vasculitic neuropathy (NSVN) is a vasculitis syndrome clinically restricted to the peripheral nervous system. Although treatment may improve prognosis, daily activities of such patients after treatment have not been well studied.
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Disulfiram eradicates tumor-initiating hepatocellular carcinoma cells in ROS-p38 MAPK pathway-dependent and -independent manners.
PLoS ONE
PUBLISHED: 01-01-2014
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Tumor-initiating cells (TICs) play a central role in tumor development, metastasis, and recurrence. In the present study, we investigated the effect of disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, toward tumor-initiating hepatocellular carcinoma (HCC) cells. DSF treatment suppressed the anchorage-independent sphere formation of both HCC cells. Flow cytometric analyses showed that DSF but not 5-fluorouracil (5-FU) drastically reduces the number of tumor-initiating HCC cells. The sphere formation assays of epithelial cell adhesion molecule (EpCAM)(+) HCC cells co-treated with p38-specific inhibitor revealed that DSF suppresses self-renewal capability mainly through the activation of reactive oxygen species (ROS)-p38 MAPK pathway. Microarray experiments also revealed the enrichment of the gene set involved in p38 MAPK signaling in EpCAM(+) cells treated with DSF but not 5-FU. In addition, DSF appeared to downregulate Glypican 3 (GPC3) in a manner independent of ROS-p38 MAPK pathway. GPC3 was co-expressed with EpCAM in HCC cell lines and primary HCC cells and GPC3-knockdown reduced the number of EpCAM(+) cells by compromising their self-renewal capability and inducing the apoptosis. These results indicate that DSF impaired the tumorigenicity of tumor-initiating HCC cells through activation of ROS-p38 pathway and in part through the downregulation of GPC3. DSF might be a promising therapeutic agent for the eradication of tumor-initiating HCC cells.
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Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.
JAMA
PUBLISHED: 12-26-2013
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Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro.
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Low-filling-factor superconducting single photon detector with high system detection efficiency.
Opt Express
PUBLISHED: 11-13-2013
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We designed, fabricated, and measured superconducting nanowire single-photon detectors (SSPDs) with low filling factor which achieve high system detection efficiency (SDE) and counting rate simultaneously. Numerical simulation reveals that high optical absorptance is possible in SSPDs even for low filing factor by tuning the device design. The SDEs of fabricated 18-50% filling factor SSPDs were measured systematically, and all SSPDs showed high SDEs of 61-80% and the lowest 18% filling factor SSPD achieved a high SDE of 69%.
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Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma.
Hepatology
PUBLISHED: 07-06-2013
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Radiofrequency ablation (RFA) is one of the treatments for hepatocellular carcinoma (HCC) and is known to enhance host immune response. However, the epitopes to which enhanced immune responses occur, the impact on patient prognosis, and the functions and phenotype of T cells induced are still unclear. To address these issues, we analyzed immune responses before and after RFA in 69 HCC patients using 11 tumor-associated antigen (TAA)-derived peptides that we identified to be appropriate to analyze HCC-specific immune responses. The immune responses were analyzed using enzyme-linked immunospot (ELISPOT) assay and tetramer assays using peripheral blood mononuclear cells. An increase in the number of TAA-specific T cells detected by interferon-? ELISPOT assays occurred in 62.3% of patients after RFA. The antigens and their epitope to which enhanced T cell responses occur were diverse, and some of them were newly induced. The number of TAA-specific T cells after RFA was associated with the prevention of HCC recurrence, and it was clarified to be predictive of HCC recurrence after RFA by univariate and multivariate analyses. The number of TAA-specific T cells after RFA was inversely correlated with the frequency of CD14+ HLA-DR(-/low) myeloid-derived suppressor cells (MDSCs). The modification of T cell phenotype was observed after RFA. The number of TAA-specific T cells at 24 weeks after RFA was decreased.
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Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis.
Amyloid
PUBLISHED: 05-28-2013
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Abstract The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients.
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Effect of age and sex differences on wild-type transthyretin amyloid formation in familial amyloidotic polyneuropathy: a proteomic approach.
Int. J. Cardiol.
PUBLISHED: 05-17-2013
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Age and sex differences are closely related to the onset of senile systemic amyloidosis (SSA) caused by wild-type (WT) transthyretin (TTR). However, the effects of these differences on the amyloid formation mechanism in familial amyloid polyneuropathy (FAP) caused by variant TTR, have remained unclear. To elucidate age and sex differences in FAP, we investigated biochemical characteristics of amyloid deposits in different tissue sites of FAP by proteomic analysis.
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Cancer stem cells in the development of liver cancer.
J. Clin. Invest.
PUBLISHED: 05-01-2013
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Liver cancer is an aggressive disease with a poor outcome. Several hepatic stem/progenitor markers are useful for isolating a subset of liver cells with stem cell features, known as cancer stem cells (CSCs). These cells are responsible for tumor relapse, metastasis, and chemoresistance. Liver CSCs dictate a hierarchical organization that is shared in both organogenesis and tumorigenesis. An increased understanding of the molecular signaling events that regulate cellular hierarchy and stemness, and success in defining key CSC-specific genes, have opened up new avenues to accelerate the development of novel diagnostic and treatment strategies. This Review highlights recent advances in understanding the pathogenesis of liver CSCs and discusses unanswered questions about the concept of liver CSCs.
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High performance fiber-coupled NbTiN superconducting nanowire single photon detectors with Gifford-McMahon cryocooler.
Opt Express
PUBLISHED: 04-24-2013
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We present high performance fiber-coupled niobium titanium nitride superconducting nanowire single photon detectors fabricated on thermally oxidized silicon substrates. The best device showed a system detection efficiency (DE) of 74%, dark count rate of 100 c/s, and full width at half maximum timing jitter of 68 ps under a bias current of 18.0 ?A with a practical Gifford-McMahon cryocooler system. We also introduced six detectors into the cryocooler and confirmed that the system DE of all detectors was higher than 67% at the dark count rate of 100 c/s.
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Marked cardiomegaly in a patient with familial amyloidotic polyneuropathy after orthotopic liver transplantation: a case study.
Pathol. Int.
PUBLISHED: 04-13-2013
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Hepatocyte-derived mutant amyloidogenic transthyretin (ATTR) causes familial amyloidotic polyneuropathy (FAP), for which orthotopic liver transplantation is an established curative treatment. However, some patients with FAP have cardiac amyloidosis after transplantation. Here, we describe a man with an autonomic disorder diagnosed as FAP ATTR Val30Met and marked cardiomegaly after liver transplantation. He underwent orthotopic liver transplantation at 49 years of age and was prescribed prednisolone to prevent graft rejection. Two years later, autonomic dysfunction and severe heart failure gradually developed. He died suddenly at 59. The autopsy revealed marked cardiomegaly (heart weight: 1020?g). Histological and ultrastructural examinations demonstrated massive amyloid deposition and unusual myocardial hypertrophic injury associated with nuclear translocation of the glucocorticoid receptor (GR). No other FAP patients without heart failure showed GR nuclear translocation. GR is a nuclear transcription factor that leads to myocardial hypertrophy, and cumulative prednisolone doses may promote marked cardiomegaly and severe cardiac amyloidosis.
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Evaluation of eligibility criteria in living donor liver transplantation for hepatocellular carcinoma by ?-SMA-positive cancer-associated fibroblasts.
Oncol. Rep.
PUBLISHED: 03-21-2013
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The eligibility criteria of liver transplantation (LT) for hepatocellular carcinoma (HCC) must clearly confirm the prognosis not only from pathological diagnosis but also from pre-operative imaging diagnosis. In the present study, we evaluated published eligibility criteria for LT based on both pre-operative imaging diagnosis and pathological diagnosis using living donor liver transplantation (LDLT) recipients at our hospital by ?-smooth muscle actin (SMA)-positive cancer-associated fibroblasts (CAFs) in HCC. The Up-to-seven (Up-to-7), Asan and Tokyo criteria were evaluated, in both overall survival and HCC disease-free survival, to be statistically significantly beneficial criteria to define post-LDLT prognosis. Recipients only within Up-to-7 criteria based on both pre-operative imaging diagnosis and pathological diagnosis survived without HCC recurrence. Recipients with proliferation of ?-SMA-positive CAFs in HCC had significantly poorer prognosis. All survival recipients without HCC recurrence, who were above the Up-to-7 criteria in pathological diagnosis, had no proliferation of ?-SMA-positive CAFs. As a result of multivariate analysis, the significant independent factors defining prognosis of recipients after LDLT for HCC were Up-to-7 criteria and proliferation of ?-SMA-positive CAFs. The ideal eligibility criteria for LDLT with HCC is Up-to-7 criteria and ?-SMA-positive CAFs was considered to be an important factor in HCC recurrence. LDLT should be limited to recipients within Up-to-7 criteria or without proliferation of ?-SMA-positive CAFs.
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The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma.
J. Hepatol.
PUBLISHED: 03-15-2013
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Recent evidence suggests that hepatocellular carcinoma can be classified into certain molecular subtypes with distinct prognoses based on the stem/maturational status of the tumor. We investigated the transcription program deregulated in hepatocellular carcinomas with stem cell features.
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Countermeasure against tailored bright illumination attack for DPS-QKD.
Opt Express
PUBLISHED: 03-14-2013
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We propose a countermeasure against the so-called tailored bright illumination attack for differential-phase-shift QKD (DPS-QKD). By monitoring a rate of coincidence detection at a pair of superconducting nanowire single-photon detectors (SSPDs) which is connected at each of the output ports of Bobs Mach-Zehnder interferometer, Alice and Bob can detect and defeat this kind of attack. We also experimentally confirmed the feasibility of this countermeasure using our 1 GHz-clocked DPS-QKD system. In the emulation of the attack, we achieved much lower power of the bright illumination light compared with the original demonstration by using a pulse stream instead of broad pulses.
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Peretinoin, an acyclic retinoid, improves the hepatic gene signature of chronic hepatitis C following curative therapy of hepatocellular carcinoma.
BMC Cancer
PUBLISHED: 03-08-2013
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The acyclic retinoid, peretinoin, has been shown to be effective for suppressing hepatocellular carcinoma (HCC) recurrence after definitive treatment in a small-scale randomized clinical trial. However, little has been documented about the mechanism by which peretinoin exerts its inhibitory effects against recurrent HCC in humans in vivo.
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MicroRNA-27a regulates lipid metabolism and inhibits hepatitis C virus replication in human hepatoma cells.
J. Virol.
PUBLISHED: 02-28-2013
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The replication and infectivity of the lipotropic hepatitis C virus (HCV) are regulated by cellular lipid status. Among differentially expressed microRNAs (miRNAs), we found that miR-27a was preferentially expressed in HCV-infected liver over hepatitis B virus (HBV)-infected liver. Gene expression profiling of Huh-7.5 cells showed that miR-27a regulates lipid metabolism by targeting the lipid synthetic transcription factor RXR? and the lipid transporter ATP-binding cassette subfamily A member 1. In addition, miR-27a repressed the expression of many lipid metabolism-related genes, including FASN, SREBP1, SREBP2, PPAR?, and PPAR?, as well as ApoA1, ApoB100, and ApoE3, which are essential for the production of infectious viral particles. miR-27a repression increased the cellular lipid content, decreased the buoyant density of HCV particles from 1.13 to 1.08 g/cm(3), and increased viral replication and infectivity. miR-27a overexpression substantially decreased viral infectivity. Furthermore, miR-27a enhanced in vitro interferon (IFN) signaling, and patients who expressed high levels of miR-27a in the liver showed a more favorable response to pegylated IFN and ribavirin combination therapy. Interestingly, the expression of miR-27a was upregulated by HCV infection and lipid overload through the adipocyte differentiation transcription factor C/EBP?. In turn, upregulated miR-27a repressed HCV infection and lipid storage in cells. Thus, this negative feedback mechanism might contribute to the maintenance of a low viral load and would be beneficial to the virus by allowing it to escape host immune surveillance and establish a persistent chronic HCV infection.
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Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs.
J Pharm Sci
PUBLISHED: 02-21-2013
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The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations.
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Association of interleukin-28B genotype and hepatocellular carcinoma recurrence in patients with chronic hepatitis C.
Clin. Cancer Res.
PUBLISHED: 02-20-2013
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Several single-nucleotide polymorphisms (SNP) in the interleukin-28B (IL-28B) locus have recently been shown to be associated with antiviral treatment efficacy for chronic hepatitis C (CHC). However, such an association with hepatocellular carcinoma (HCC) is unkno3 we investigated the association between the IL-28B genotype and the biology and clinical outcome of patients with HCC receiving curative treatment.
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Gene expression profiling of hepatitis B- and hepatitis C-related hepatocellular carcinoma using graphical Gaussian modeling.
Genomics
PUBLISHED: 02-09-2013
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Gene expression profiling of hepatocellular carcinoma (HCC) and background liver has been studied extensively; however, the relationship between the gene expression profiles of different lesions has not been assessed.
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Bilateral basal ganglia lesions as initial manifestation of CNS invasion in adult T-cell leukemia.
J. Neurol. Sci.
PUBLISHED: 01-25-2013
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We describe the case of a 67-year-old man who exhibited unsteadiness in walking, topographical disorientation, and urinary incontinence. Neurological examination revealed somnolence and mild weakness in the lower limbs with slight rigidity in the upper limbs. Cerebrospinal fluid examination showed pleocytosis with "flower cells" and an extremely high level of soluble interleukin-2 receptor. T2-weighted brain imaging revealed symmetrical high-intensity lesions in the bilateral caudate putamen. Positron emission tomography demonstrated intense uptake of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose in the same region. He was diagnosed with central nervous system invasion by adult T-cell leukemia (ATL) and received chemotherapy. Interestingly, chemotherapy ameliorated the lesions and terminally caused the gray matter itself to atrophy in the bilateral caudate nuclei, which may be evidence for the direct infiltration of ATL tumors.
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Impact of antibodies against amyloidogenic transthyretin (ATTR) on phenotypes of patients with familial amyloidotic polyneuropathy (FAP) ATTR Valine30Methionine.
Clin. Chim. Acta
PUBLISHED: 01-24-2013
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This study investigated whether a relationship exists between the presence of de novo antibodies and the clinical manifestations of familial amyloidotic polyneuropathy (FAP).
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Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma.
Hepatology
PUBLISHED: 01-18-2013
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Recent evidence suggests that hepatocellular carcinoma (HCC) is organized by a subset of cells with stem cell features (cancer stem cells; CSCs). CSCs are considered a pivotal target for the eradication of cancer, and liver CSCs have been identified by the use of various stem cell markers. However, little information is known about the expression patterns and characteristics of marker-positive CSCs, hampering the development of personalized CSC-targeted therapy. Here, we show that CSC markers EpCAM and CD90 are independently expressed in liver cancer. In primary HCC, EpCAM+ and CD90+ cells resided distinctively, and gene-expression analysis of sorted cells suggested that EpCAM+ cells had features of epithelial cells, whereas CD90+ cells had those of vascular endothelial cells. Clinicopathological analysis indicated that the presence of EpCAM+ cells was associated with poorly differentiated morphology and high serum alpha-fetoprotein (AFP), whereas the presence of CD90+ cells was associated with a high incidence of distant organ metastasis. Serial xenotransplantation of EpCAM+ /CD90+ cells from primary HCCs in immune-deficient mice revealed rapid growth of EpCAM+ cells in the subcutaneous lesion and a highly metastatic capacity of CD90+ cells in the lung. In cell lines, CD90+ cells showed abundant expression of c-Kit and in vitro chemosensitivity to imatinib mesylate. Furthermore, CD90+ cells enhanced the motility of EpCAM+ cells when cocultured in vitro through the activation of transforming growth factor beta (TGF-?) signaling, whereas imatinib mesylate suppressed TGFB1 expression in CD90+ cells as well as CD90+ cell-induced motility of EpCAM+ cells.
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Quantitative estimation of urate transport in nephrons in relation to urinary excretion employing benzbromarone-loading urate clearance tests in cases of hyperuricemia.
Nephron Extra
PUBLISHED: 09-22-2011
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A four-component system for urate transport in nephrons has been proposed and widely investigated by various investigators studying the mechanisms underlying urinary urate excretion. However, quantitative determinations of urate transport have not been clearly elucidated yet.
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Sporadic juvenile amyotrophic lateral sclerosis caused by mutant FUS/TLS: possible association of mental retardation with this mutation.
J. Neurol.
PUBLISHED: 08-16-2011
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We present two cases of patients with juvenile amyotrophic lateral sclerosis (ALS), who had no history of familial ALS. The symptoms of both patients started as weakness of the unilateral upper limb and neck, and extended to bulbar and respiratory weakness in a relatively short period. Of note, the first patient was mentally retarded before the onset of weakness. Fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene analyses revealed mutations of p. G492EfsX527 (c. 1475delG), which is a novel deletion/frameshift mutation, in the first patient and p. R514S mutation (c. 1542G > T) in the second patient. Molecular analysis revealed that the mutant FUS/TLS, especially the deletion/frameshift mutation, showed significant cytoplasmic localization in transfected motor neuron-like cells. Our findings suggest the association of mental retardation with the FUS/TLS mutation. Further investigation, including the effect of FUS/TLS on cognitive function, would aid better understanding of FUS/TLS proteinopathies.
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Supersaturation-nucleation behavior of poorly soluble drugs and its impact on the oral absorption of drugs in thermodynamically high-energy forms.
J Pharm Sci
PUBLISHED: 06-08-2011
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In order to better understand the oral absorption behavior of poorly water-soluble drugs, their supersaturation-nucleation behavior was characterized in fasted state simulated intestinal fluid. The induction time (t(ind)) for nucleation was measured for four model drugs: itraconazole, erlotinib, troglitazone, and PLX4032. Supersaturated solutions were prepared by solvent shift method, and nucleation initiation was monitored by ultraviolet detection. The relationship between t(ind) and degree of supersaturation was analyzed in terms of classical nucleation theory. The defined supersaturation stability proved to be compound specific. Clinical data on oral absorption were investigated for drugs in thermodynamically high-energy forms such as amorphous forms and salts and was compared with in vitro supersaturation-nucleation characteristics. Solubility-limited maximum absorbable dose was proportionate to intestinal effective drug concentrations, which are related to supersaturation stability and thermodynamic solubility. Supersaturation stability was shown to be an important factor in determining the effect of high-energy forms. The characterization of supersaturation-nucleation behavior by the presented method is, therefore, valuable for assessing the potential absorbability of poorly water-soluble drugs.
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Solvent shift method for anti-precipitant screening of poorly soluble drugs using biorelevant medium and dimethyl sulfoxide.
Int J Pharm
PUBLISHED: 06-01-2011
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96-well plate based anti-precipitant screening using bio-relevant medium FaSSIF (fasted-state simulated small intestinal fluid) is a useful technique for discovering anti-precipitants that maintain supersaturation of poorly soluble drugs. In a previous report, two disadvantages of the solvent evaporation method (solvent casting method) were mentioned: precipitation during the evaporation process and the use of volatile solvents to dissolve compounds. In this report, we propose a solvent shift method using DMSO (dimethyl sulfoxide). Initially, the drug substance was dissolved in DMSO at a high concentration and diluted with FaSSIF that contained anti-precipitants. To evaluate the validity of the method, itraconazole (ITZ) was used as the poorly soluble model drug. The solvent shift method resolved the disadvantages of the evaporation method, and AQOAT (HPMC-AS) was found as the most appropriate anti-precipitant for ITZ in a facile and expeditious manner when compared with the solvent evaporation method. In the large scale JP paddle method, AQOAT-based solid dispersion maintained a higher concentration than Tc-5Ew (HPMC)-based formulation; this result corresponded well with the small scale of the solvent shift method.
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Spinal multifocal amyloidosis derived from wild-type transthyretin.
Amyloid
PUBLISHED: 06-01-2011
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Abstract Spinal amyloidosis can occur as a part of systemic amyloidosis or as localized amyloidomas. However, the exact pathogenesis of the spinal amyloidosis remains to be fully understood. Transthyretin (TTR) is an amyloidogenic protein causing two kinds of amyloid diseases. One is senile systemic amyloidosis (SSA), which is caused by wild-type (WT) TTR and primarily affects cardiac functions. The other type is familial amyloidosis, which is mainly induced by mutated TTR. We report here the first case of multifocal spinal TTR amyloidosis derived from WT TTR with radiculomyelopathy and destructive spondylosis. The data and clinical manifestations suggest that the patient may develop SSA. Clinical manifestations of TTR-related amyloidosis may vary more than we previously thought. In spinal amyloidosis, WT TTR is one of the candidate precursor proteins for the disease.
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[Familial amyloid polyneuropathy].
Brain Nerve
PUBLISHED: 05-27-2011
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Familial amyloid polyneuropathy (FAP), a fatal disorder inherited in an autosomal dominant fashion, is characterized by systemic accumulation of polymerized transthyretin (TTR) in the peripheral nerves and systemic organs. Polyneuropathy is often a major manifestation of FAP. Although FAP was considered to be an endemic disorder, the advanced biochemical and molecular genetic analyses have shown worldwide occurrence. More than 100 different points of single or double mutations, or a deletion in the TTR gene, have been reported, and several different phenotypes of FAP have been documented, even for the same mutation in the TTR gene. Liver transplantation, which stops the production of amyloidogenic TTR in blood and replaces it with normal TTR, has been considered as an acceptable treatment for FAP. However, continuous amyloid deposition can occur from wild-type (normal) TTR in some patients. Currently, research an the inhibition of amyloid deposition by small organic molecules that are hypothesized to affect the fibril-forming ability of TTR is underway.
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Randomized, phase II study comparing interferon combined with hepatic arterial infusion of fluorouracil plus cisplatin and fluorouracil alone in patients with advanced hepatocellular carcinoma.
Oncology
PUBLISHED: 05-26-2011
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This randomized phase II trial compared the response rates to treatment with interferon (IFN) combined with hepatic arterial infusion of fluorouracil (FU) plus cisplatin (CDDP) or FU alone in patients with advanced hepatocellular carcinoma (HCC).
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Cerebral amyloid angiopathy-related inflammation presenting with steroid-responsive higher brain dysfunction: case report and review of the literature.
J Neuroinflammation
PUBLISHED: 05-20-2011
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A 56-year-old man noticed discomfort in his left lower limb, followed by convulsion and numbness in the same area. Magnetic resonance imaging (MRI) showed white matter lesions in the right parietal lobe accompanied by leptomeningeal or leptomeningeal and cortical post-contrast enhancement along the parietal sulci. The patient also exhibited higher brain dysfunction corresponding with the lesions on MRI. Histological pathology disclosed ?-amyloid in the blood vessels and perivascular inflammation, which highlights the diagnosis of cerebral amyloid angiopathy (CAA)-related inflammation. Pulse steroid therapy was so effective that clinical and radiological findings immediately improved.CAA-related inflammation is a rare disease, defined by the deposition of amyloid proteins within the leptomeningeal and cortical arteries associated with vasculitis or perivasculitis. Here we report a patient with CAA-related inflammation who showed higher brain dysfunction that improved with steroid therapy. In cases with atypical radiological lesions like our case, cerebral biopsy with histological confirmation remains necessary for an accurate diagnosis.
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Identification of a secretory protein c19orf10 activated in hepatocellular carcinoma.
Int. J. Cancer
PUBLISHED: 04-13-2011
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The identification of genes involved in tumor growth is crucial for the development of inventive anticancer treatments. Here, we have cloned a 17-kDa secretory protein encoded by c19orf10 from hepatocellular carcinoma (HCC) serial analysis of gene expression libraries. Gene expression analysis indicated that c19orf10 was overexpressed in approximately two-thirds of HCC tissues compared to the adjacent noncancerous liver tissues, and its expression was significantly positively correlated with that of alpha-fetoprotein (AFP). Overexpression of c19orf10 enhanced cell proliferation of AFP-negative HLE cells, whereas knockdown of c19orf10 inhibited cell proliferation of AFP-positive Hep3B and HuH7 cells along with G1 cell cycle arrest. Supplementation of recombinant c19orf10 protein in culture media enhanced cell proliferation in HLE cells, and this effect was abolished by the addition of antibodies developed against c19orf10. Intriguingly, c19orf10 could regulate cell proliferation through the activation of Akt/mitogen-activated protein kinase pathways. Taken together, these data suggest that c19orf10 might be one of the growth factors and potential molecular targets activated in HCC.
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Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma.
Hepatology
PUBLISHED: 04-12-2011
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Many tumor-associated antigens (TAAs) recognized by cytotoxic T cells (CTLs) have been identified during the last two decades and some of them have been used in clinical trials. However, there are very few in the field of immunotherapy for hepatocellular carcinoma (HCC) because there have not been comparative data regarding CTL responses to various TAAs. In the present study, using 27 peptides derived from 14 different TAAs, we performed comparative analysis of various TAA-specific T-cell responses in 31 HCC patients to select useful antigens for immunotherapy and examined the factors that affect the immune responses to determine a strategy for more effective therapy. Twenty-four of 31 (77.4%) HCC patients showed positive responses to at least one TAA-derived peptide in enzyme-linked immunospot assay. The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. HCC treatments enhanced TAA-specific immune responses with an increased number of memory T cells and induced de novo T-cell responses to lymphocyte-specific protein tyrosine kinase, human epidermal growth factor receptor type 2, p53, and hTERT. Blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) resulted in unmasking of TAA-specific immune responses by changing cytokine and chemokine profiles of peripheral blood mononuclear cells stimulated by TAA-derived peptides.
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Molecular mechanisms of hepatocarcinogenesis in chronic hepatitis C virus infection.
J. Gastroenterol. Hepatol.
PUBLISHED: 03-30-2011
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Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) and chronic liver disease worldwide. Recent developments and advances in HCV replication systems in vitro and in vivo, transgenic animal models, and gene expression profiling approaches have provided novel insights into the mechanisms of HCV replication. They have also helped elucidate host cellular responses, including activated/inactivated signaling pathways, and the relationship between innate immune responses by HCV infection and host genetic traits. However, the mechanisms of hepatocyte malignant transformation induced by HCV infection are still largely unclear, most likely due to the heterogeneity of molecular paths leading to HCC development in each individual. In this review, we summarize recent advances in knowledge about the mechanisms of hepatocarcinogenesis induced by HCV infection.
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Frequency of CD45RO+ subset in CD4+CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma.
Cancer Lett.
PUBLISHED: 03-11-2011
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The purpose of this study was to assess the properties of CD4+CD25(high/low/negative) T cell subsets and analyze their relation with dendritic cells (DCs) in patients with hepatocellular carcinoma (HCC). In HCC patients, the prevalence of CD45RO+ cells in CD4+CD25(high) T cells was increased and associated with higher frequencies of plasmacytoid DCs. Larger proportions of this T cell subset were detected in the patients with larger tumor burdens. These results suggest that increased frequencies of the CD45RO+ subset in CD4+CD25(high) Tregs in HCC patients may establish the immunosuppressive environment cooperatively with tolerogenic plasmacytoid DCs to promote disease progression of liver cancer.
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Midsubtemporal ridge as a predictor of the lateral loop formed by the maxillary nerve and mandibular nerve: a cadaveric morphological study.
Neurosurgery
PUBLISHED: 02-25-2011
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The lateral loop formed by the maxillary nerve (V2) and the mandibular nerve (V3) consists of a part of the far lateral triangle of the cavernous sinus. Because this triangle becomes a surgical corridor of the preauricular infratemporal fossa approach and a landmark of the extradural approach for the ganglion-type trigeminal schwannomas, identification of the lateral loop has important implications at the early stage of middle cranial base surgery. We realized that a bony ridge usually existed just lateral to the lateral loop.
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Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C.
Gastroenterology
PUBLISHED: 02-21-2011
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Patients with advanced chronic hepatitis C (CH-C) often are malnourished, but the effects of malnutrition on interferon (IFN) signaling and response to treatment have not been determined. We assessed the importance of the nutritional state of the liver on IFN signaling and treatment response.
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Frozen water phase method for logD measurement using a 96-well plate.
Talanta
PUBLISHED: 02-08-2011
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In this study, a frozen water phase method for logD measurement using a 96-well plate was developed. In the case of logD measurement of compounds, the problem of octanol contamination often occurs; in lipophilic compounds, the concentration of the octanol phase is much higher than that of the water phase. When the water phase is separated from the octanol phase, a small amount of octanol phase contamination could strongly influence the concentration of the water phase. To avoid this problem, the frozen water phase method was developed. The water phase was frozen in liquid nitrogen and then the unfrozen octanol phase was removed. To remove the portion of the octanol remaining on the frozen water phase, the surface of the frozen water phase was washed with octanol and water/ethanol (50/50, v/v). The validity of the method was confirmed by results of commercially available drugs at the logD range from 0 to 4. Further, it was found that this method had the ability to evaluate the pH-logD profile of compounds in the range from pH 2 to pH 12. As a result, we developed the convenient and accurate method that is effective in preventing contamination with a wide dynamic range.
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Computed tomography imaging of transferrin targeting liposomes encapsulating both boron and iodine contrast agents by convection-enhanced delivery to F98 rat glioma for boron neutron capture therapy.
Neurosurgery
PUBLISHED: 01-29-2011
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To achieve potent tumor-selective antitumor efficacy by boron neutron capture therapy (BNCT), it is important to have a significant differential uptake of 10B between tumor cells and normal cells. This should enable BNCT to reduce damage to normal tissues compared with other radiation therapies.
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Relationship between amyloid deposition and intracellular structural changes in familial amyloidotic polyneuropathy.
Hum. Pathol.
PUBLISHED: 01-23-2011
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Transthyretin-related familial amyloidotic polyneuropathy is a systemic amyloidosis caused by mutations in the transthyretin gene. Extracellular deposition of amyloid is the common pathologic hallmark of amyloidoses including Alzheimer disease, AL amyloidosis, AA amyloidosis, and familial amyloidotic polyneuropathy. However, the exact relationship between amyloid deposition and cell death has not yet been clarified. To elucidate this relationship, we studied the effect of transthyretin amyloid fibrils and prefibrillar aggregates on cells by using autopsy tissues obtained from 8 patients with familial amyloidotic polyneuropathy, as well as cultured cell lines. Ultrastructural studies of amyloid-laden cardiomyocytes showed that intracellular structural changes correlated with the degree of amyloid deposition and may reflect metabolic disturbances caused by physical limitations imposed by the amyloid deposits. Amyloid-laden vascular endothelial cells, mesangial cells, smooth muscle cells, Schwann cells, and cardiomyocytes, however, had well-preserved cell nuclei and showed no apoptotic changes, even when cells were completely surrounded by prefibrillar transthyretin aggregates and amyloid fibrils. Synthesized prefibrillar transthyretin aggregates, transthyretin fibrils, and amyloid fibrils obtained from patients with familial amyloidotic polyneuropathy evidenced no cytotoxicity in cell culture experiments. Our data thus indicate that neither transthyretin amyloid fibrils nor prefibrillar transthyretin aggregates directly induced apoptosis. However, cellular metabolic disturbances caused by cells being physically confined by amyloid deposits may induce cell degeneration.
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Wnt/beta-catenin signaling activates microRNA-181 expression in hepatocellular carcinoma.
Cell Biosci
PUBLISHED: 01-18-2011
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Hepatocellular carcinoma (HCC) is a malignant cancer with an observable heterogeneity and microRNAs are functionally associated with the tumorigenesis of HCC. We recently identified that EpCAM (CD326)-positive cells isolated from alpha-fetoprotein (AFP)-positive HCC samples are hepatic cancer stem cells (HepCSCs). EpCAM+AFP+ HepCSCs have an activated Wnt/?-catenin signaling with a parallel increased expression of all four microRNA-181 family members. We hypothesized that Wnt/?-catenin signaling transcriptionally activates microRNA-181s in HCC.
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Photon level crosstalk between parallel fibers installed in urban area.
Opt Express
PUBLISHED: 10-14-2010
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We estimate the channel characteristics of field-installed dark fibers at single photon levels for quantum key distribution (QKD). Measured fibers are telecom single-mode dark fibers over 45 km connecting a center and suburbs of Tokyo. Their total losses are about 14dB, and 50% of the whole lengths are aerial lines. We find that stray light from other public internet fibers is dominant and crosstalk occurs at bending points in laying cables. These results mean the crosstalk from public networks can increase the bit error rate in the QKD system, and imply an underlying information leakage through an adjacent covered-fiber.
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Targeted disruption of Ing2 results in defective spermatogenesis and development of soft-tissue sarcomas.
PLoS ONE
PUBLISHED: 08-09-2010
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ING2 (inhibitor of growth family, member 2) is a member of the plant homeodomain (PHD)-containing ING family of putative tumor suppressors. As part of mSin3A-HDAC corepressor complexes, ING2 binds to tri-methylated lysine 4 of histone H3 (H3K4me3) to regulate chromatin modification and gene expression. ING2 also functionally interacts with the tumor suppressor protein p53 to regulate cellular senescence, apoptosis and DNA damage response in vitro, and is thus expected to modulate carcinogenesis and aging. Here we investigate the developmental and physiological functions of Ing2 through targeted germline disruption. Consistent with its abundant expression in mouse and human testes, male mice deficient for Ing2 showed abnormal spermatogenesis and were infertile. Numbers of mature sperm and sperm motility were significantly reduced in Ing2(-/-) mice (?2% of wild type, P<0.0001 and ?10% of wild type, P<0.0001, respectively). Their testes showed degeneration of seminiferous tubules, meiotic arrest before pachytene stage with incomplete meiotic recombination, induction of p53, and enhanced apoptosis. This phenotype was only partially abrogated by concomitant loss of p53 in the germline. The arrested spermatocytes in Ing2(-/-) testes were characterized by lack of specific HDAC1 accumulation and deregulated chromatin acetylation. The role of Ing2 in germ cell maturation may extend to human ING2 as well. Using publicly available gene expression datasets, low expression of ING2 was found in teratozoospermic sperm (>3-fold reduction) and in testes from patients with defective spermatogenesis (>7-fold reduction in Sertoli-cell only Syndrome). This study establishes ING2 as a novel regulator of spermatogenesis functioning through both p53- and chromatin-mediated mechanisms, suggests that an HDAC1/ING2/H3K4me3-regulated, stage-specific coordination of chromatin modifications is essential to normal spermatogenesis, and provides an animal model to study idiopathic and iatrogenic infertility in men. In addition, a bona fide tumor suppressive role of Ing2 is demonstrated by increased incidence of soft-tissue sarcomas in Ing2(-/-) mice.
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Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial.
Lancet Neurol
PUBLISHED: 08-04-2010
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Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy.
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Differential gene expression profiling in blood from patients with digestive system cancers.
Biochem. Biophys. Res. Commun.
PUBLISHED: 07-28-2010
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To develop a non-invasive and sensitive diagnostic test for cancer using peripheral blood, we evaluated gene expression profiling of blood obtained from patients with cancer of the digestive system and normal subjects. The expression profiles of blood-derived total RNA obtained from 39 cancer patients (11 colon cancer, 14 gastric cancer, and 14 pancreatic cancer) was clearly different from those obtained from 15 normal subjects. By comparing the gene expression profiles of cancer patients and normal subjects, 25 cancer-differentiating genes (p<5.0 x 10(-6) and fold differences >3) were identified and an "expression index" deduced from the expression values of these genes differentiated the validation cohort (11 colon cancer, 8 gastric cancer, 18 pancreatic cancer, and 15 normal subjects) into cancer patients and normal subjects with 100% (37/37) and 87% (13/15) accuracy, respectively. Although, the expression profiles were not clearly different between the cancer patients, some characteristic genes were identified according to the stage and species of the cancer. Interestingly, many immune-related genes such as antigen presenting, cell cycle accelerating, and apoptosis- and stress-inducing genes were up-regulated in cancer patients, reflecting the active turnover of immune regulatory cells in cancer patients. These results showed the potential relevance of peripheral blood gene expression profiling for the development of new diagnostic examination tools for cancer patients.
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Multichannel SNSPD system with high detection efficiency at telecommunication wavelength.
Opt Lett
PUBLISHED: 07-03-2010
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We developed a four-channel superconducting nanowire single-photon detector system based on a Gifford-McMahon cryocooler. All channels showed a system detection efficiency (DE) (at a 100 Hz dark-count rate) higher than 16% at 1550 nm wavelength, and the best channel showed a system DE of 21% and 30% at 1550 and 1310 nm wavelength, respectively.
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Oncostatin m renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-Fluorouracil by inducing hepatocytic differentiation.
Cancer Res.
PUBLISHED: 05-18-2010
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Recent evidence suggests that a certain type of hepatocellular carcinoma (HCC) is hierarchically organized by a subset of cells with stem cell features (cancer stem cells; CSC). Although normal stem cells and CSCs are considered to share similar self-renewal programs, it remains unclear whether differentiation programs are also maintained in CSCs and effectively used for tumor eradication. In this study, we investigated the effect of oncostatin M (OSM), an interleukin 6-related cytokine known to induce the differentiation of hepatoblasts into hepatocytes, on liver CSCs. OSM receptor expression was detected in the majority of epithelial cell adhesion molecule-positive (EpCAM(+)) HCC with stem/progenitor cell features. OSM treatment resulted in the induction of hepatocytic differentiation of EpCAM(+) HCC cells by inducing signal transducer and activator of transcription 3 activation, as determined by a decrease in stemness-related gene expression, a decrease in EpCAM, alpha-fetoprotein and cytokeratin 19 protein expressions, and an increase in albumin protein expression. OSM-treated EpCAM(+) HCC cells showed enhanced cell proliferation with expansion of the EpCAM-negative non-CSC population. Noticeably, combination of OSM treatment with the chemotherapeutic agent 5-fluorouracil (5-FU), which eradicates EpCAM-negative non-CSCs, dramatically increased the number of apoptotic cells in vitro and suppressed tumor growth in vivo compared with either saline control, OSM, or 5-FU treatment alone. Taken together, our data suggest that OSM could be effectively used for the differentiation and active cell division of dormant EpCAM(+) liver CSCs, and the combination of OSM and conventional chemotherapy with 5-FU efficiently eliminates HCC by targeting both CSCs and non-CSCs.
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Asialoerythropoietin attenuates neuronal cell death in the hippocampal CA1 region after transient forebrain ischemia in a gerbil model.
Neurol. Res.
PUBLISHED: 05-04-2010
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Systemic administration of high-dose recombinant human erythropoietin (rhEPO) is known to attenuate ischemic injury. However, high-dose rhEPO might aggravate ischemic lesions by increasing blood viscosity because of its erythropoietic effects. Asialoerythropoietin (asialoEPO), an EPO derivative with an extremely short plasma half-life, has considerably lesser erythropoietic effect than that of naive EPO. We attempted to determine whether asialoEPO exerts the same neuroprotective effect as naive EPO in a gerbil transient forebrain ischemia model.
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A liver-derived secretory protein, selenoprotein P, causes insulin resistance.
Cell Metab.
PUBLISHED: 04-29-2010
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The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral tissues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes.
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Differential interferon signaling in liver lobule and portal area cells under treatment for chronic hepatitis C.
J. Hepatol.
PUBLISHED: 04-29-2010
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The mechanisms of treatment resistance to interferon (IFN) and ribavirin (Rib) combination therapy for hepatitis C virus (HCV) infection are not known. This study aims to gain insight into these mechanisms by exploring hepatic gene expression before and during treatment.
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Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C.
Gastroenterology
PUBLISHED: 04-05-2010
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Multiple viral and host factors are related to the treatment response to pegylated-interferon and ribavirin combination therapy; however, the clinical relevance and relationship of these factors have not yet been fully evaluated.
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[Molecular pathogenesis of hepatocellular carcinoma].
Gan To Kagaku Ryoho
PUBLISHED: 01-21-2010
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Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC nearly almost always develops in connection with chronic hepatitis or liver cirrhosis, mainly due to hepatitis B virus or hepatitis C virus infection. Several factors are supposed to play key roles in the development of HCC, such as aberrant viral protein expression, genomic instability with/without insertions of viral DNAs, gene mutations, epigenetic gene modification, oxidative stress, and alteration of the microenvironment including inflammation, fibrosis, and emergence of stem/progenitor cells as a result of repeated necrosis and regeneration of hepatocytes. The elucidation of molecular mechanisms of hepatocarcinogenesis has successfully provided small molecule inhibitors targeting aberrantly activated signaling in HCC. Development of novel classification systems based on the molecular profiles and drug sensitivities against molecularly targeted compounds is currently underway to facilitate novel strategies for effective eradication of HCC.
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Comprehensive gene expression analysis of 5-end of mRNA identified novel intronic transcripts associated with hepatocellular carcinoma.
Genomics
PUBLISHED: 01-14-2010
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To elucidate the molecular feature of human hepatocellular carcinoma (HCC), we performed 5-end serial analysis of gene expression (5SAGE), which allows genome-wide identification of transcription start sites in addition to quantification of mRNA transcripts. Three 5SAGE libraries were generated from normal human liver (NL), non-B, non-C HCC tumor (T), and background non-tumor tissues (NT). We obtained 226,834 tags from these libraries and mapped them to the genomic sequences of a total of 8,410 genes using RefSeq database. We identified several novel transcripts specifically expressed in HCC including those mapped to the intronic regions. Among them, we confirmed the transcripts initiated from the introns of a gene encoding acyl-coenzyme A oxidase 2 (ACOX2). The expression of these transcript variants were up-regulated in HCC and showed a different pattern compared with that of ordinary ACOX2 mRNA. The present results indicate that the transcription initiation of a subset of genes may be distinctively altered in HCC, which may suggest the utility of intronic RNAs as surrogate tumor markers.
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dUTP pyrophosphatase expression correlates with a poor prognosis in hepatocellular carcinoma.
Liver Int.
PUBLISHED: 11-30-2009
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Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis, partly owing to the lack of biomarkers that support its classification in line with its malignant nature. To discover a novel molecular marker that is related to the efficacy of treatment for HCC and its biological nature, we performed serial analysis of gene expression (SAGE) in HCC, normal liver and cirrhotic liver tissues.
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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.