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Find video protocols related to scientific articles indexed in Pubmed.
Eye movements during emotion recognition in faces.
J Vis
PUBLISHED: 11-20-2014
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When distinguishing whether a face displays a certain emotion, some regions of the face may contain more useful information than others. Here we ask whether people differentially attend to distinct regions of a face when judging different emotions. Experiment 1 measured eye movements while participants discriminated between emotional (joy, anger, fear, sadness, shame, and disgust) and neutral facial expressions. Participant eye movements primarily fell in five distinct regions (eyes, upper nose, lower nose, upper lip, nasion). Distinct fixation patterns emerged for each emotion, such as a focus on the lips for joyful faces and a focus on the eyes for sad faces. These patterns were strongest for emotional faces but were still present when viewers sought evidence of emotion within neutral faces, indicating a goal-driven influence on eye-gaze patterns. Experiment 2 verified that these fixation patterns tended to reflect attention to the most diagnostic regions of the face for each emotion. Eye movements appear to follow both stimulus-driven and goal-driven perceptual strategies when decoding emotional information from a face.
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Application of Modeling and Simulation to a Long-Term Clinical Trial: A Direct Comparison of Simulated Data and Data Actually Observed in Japanese Osteoporosis Patients Following 3-Year Ibandronate Treatment.
Clin Pharmacokinet
PUBLISHED: 11-19-2014
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Ibandronate, a nitrogen-containing bisphosphonate, is a bone resorption inhibitor widely used to prevent and treat osteoporosis. To optimize the design for a long-term clinical study of ibandronate, modeling and simulation (M&S) was performed based on the result of population pharmacodynamic analysis using the data of a short-term clinical study. A population pharmacodynamic model was constructed by the urinary C-terminal telopeptide of type I collagen (uCTx) and the lumbar spine bone mineral density (BMD) data obtained in clinical studies, including a phase II study of Japanese osteoporosis patients treated with ibandronate for 6 months. Changes in BMD over a period of 3 years were simulated from the population pharmacodynamic parameters of the patients in this phase II study. The relationship between uCTx and BMD was well described by this modeling. The functions of disease progression and supplemental treatment were incorporated into the model to simulate a long-term clinical study with high accuracy. A long-term clinical study with a 3-year treatment was conducted after this M&S. The percentage change from baseline in observed BMD values were found to be similar to the prospectively simulated values. This study showed that M&S could be a useful and powerful tool for designing and conducting long-term clinical studies when carried out in the following sequence: (1) conduct a short-term clinical study; (2) perform M&S; and (3) conduct the long-term clinical study. Application of this procedure to various other treatment agents will establish the usefulness of M&S for long-term clinical studies and bring further efficiencies to drug development.
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Grade 4 epistaxis in a woman with metastatic breast cancer treated with bevacizumab: a case report.
J Nippon Med Sch
PUBLISHED: 11-14-2014
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We describe a 39-year-old woman with metastatic breast cancer who had grade 4 epistaxis induced by bevacizumab. The patient visited our outpatient clinic with complaints of a lump in her right breast, fatigue, dyspnea, abdominal distention, appetite loss, and weight loss of 10 kg over 1 year. Liver dysfunction was detected, with elevated levels of aspartate aminotransferase (271 IU/L), alanine aminotransferase (100 IU/L), alkaline phosphatase (4,205 IU/L), total bilirubin (2.7 mg/dL), and direct bilirubin (2.1 mg/dL). A secondary liver tumor that occupied most of the liver volume was found, and bone metastasis, ascites, and pleural effusion were also discovered. The Eastern Cooperative Oncology Group performance status was 2. A core needle biopsy of the right breast tumor revealed invasive ductal carcinoma of the breast (nuclear grade 1) that was positive for estrogen receptor and progesterone receptor and negative for human epidermal growth factor receptor 2 overexpression and had a high Ki-67 score. We chose combination chemotherapy with paclitaxel (80 mg/m(2) on days 1, 8, and 15) and bevacizumab (10 mg/kg on days 1 and 15) for 28 days (1 cycle). After completion of the first cycle of chemotherapy, the ascites and pleural effusion decreased, and the metastatic liver tumor shrank. The performance status improved from 2 to 1. On day 3 of the third cycle of chemotherapy, however, she began having persistent epistaxis. On day 6, she lost consciousness and was transported to the emergency room of our hospital. The hemoglobin level was 5.6 g/dL. Blood transfusion and endoscopic hemostasis were immediately started. Bevacizumab was discontinued, and paclitaxel alone was continued; after this change, epistaxis did not recur.
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Podoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutation.
Clin. Cancer Res.
PUBLISHED: 11-13-2014
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Purpose: The biological characteristics of microenvironmental constituents, especially cancer-associated fibroblasts (CAFs), can be key regulators of the cellular sensitivity to molecular-targeted therapy. EGFR tyrosine kinase inhibitors (EGFR-TKIs) have marked therapeutic effects against non-small cell lung cancer (NSCLC) with EGFR mutations, but some patients have exhibited primary resistance to EGFR-TKIs. We recently reported that podoplanin (PDPN)-positive fibroblasts are associated with a tumor-promoting phenotype of CAFs in lung adenocarcinoma. The aim of this study was to evaluate whether the susceptibility of NSCLC to EGFR-TKIs could be affected by PDPN-expressing CAFs. Experimental Design: We evaluated the EGFR-TKI sensitivity of EGFR-mutant lung adenocarcinoma cell lines co-cultured with PDPN-expressing CAFs. We also examined the association between the expression of PDPN in CAFs in surgical specimens and EGFR-TKI response of postoperative recurrent patients with EGFR mutations (N = 106). Results: Lung adenocarcinoma cell lines became more resistant to EGFR-TKI when co-cultured with PDPN-expressing CAFs, compared with control CAFs in vitro. The knockdown of PDPN-expression on CAFs cancelled the resistance to EGFR-TKIs in cancer cells. Compared with control CAFs, the cancer cells that were co-cultured with PDPN-positive CAFs continued to exhibit significantly higher p-ERK levels after treatment with gefitinib. Furthermore, postoperative recurrent patients with PDPN-positive CAFs had a significantly lower overall response rate to EGFR-TKIs, compared with those with PDPN-negative CAFs (53% vs 83%, P < 0.01). Conclusions: PDPN-positive CAFs plays an important role in primary resistance to EGFR-TKIs and may be an ideal therapeutic target for use in combination therapy with EGFR-TKIs.
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Surrounding Cells Affect the Gene Expression Pattern of Human Beta-defensins in Squamous Cell Carcinoma In Vitro.
Anticancer Res.
PUBLISHED: 11-05-2014
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Defensins are basic peptides involved in non-immune bio-defense mechanisms in a normal epithelium. Human oral squamous cell carcinoma cells (OSCC) also produce human beta-defensins (HBDs), although their exact function is not clear. This study aimed to analyze the variation in gene expression levels of hBDs in co-cultures of OSCC with murine cells.
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Direct Quantification of Loop Interaction and ?-? Stacking for G-Quadruplex Stability at the Submolecular Level.
J. Am. Chem. Soc.
PUBLISHED: 10-22-2014
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The well-demonstrated biological functions of DNA G-quadruplex inside cells call for small molecules that can modulate these activities by interacting with G-quadruplexes. However, the paucity of the understanding of the G-quadruplex stability contributed from submolecular elements, such as loops and tetraguanine (G) planes (or G-quartets), has hindered the development of small-molecule binders. Assisted by click chemistry, herein, we attached pulling handles via two modified guanines in each of the three G-quartets in human telomeric G-quadruplex. Mechanical unfolding using these handles revealed that the loop interaction contributed more to the G-quadruplex stability than the stacking of G-quartets. This result was further confirmed by the binding of stacking ligands, such as telomestatin derivatives, which led to similar mechanical stability for all three G-quartets by significant reduction of loop interactions for the top and bottom G-quartets. The direct comparison of loop interaction and G-quartet stacking in G-quadruplex provides unprecedented insights for the design of more efficient G-quadruplex-interacting molecules. Compared to traditional experiments, in which mutations are employed to elucidate the roles of specific residues in a biological molecule, our submolecular dissection offers a complementary approach to evaluate individual domains inside a molecule with fewer disturbances to the native structure.
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Thromboelastometry-guided intraoperative haemostatic management reduces bleeding and red cell transfusion after paediatric cardiac surgery.
Br J Anaesth
PUBLISHED: 10-10-2014
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Thromboelastometric evaluation of coagulation might be useful for prediction and management of bleeding after paediatric cardiac surgery. We tested the hypothesis that the use of a thromboelastometry-guided algorithm for blood product management reduces blood loss and transfusion requirements.
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Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma.
Cancer Res.
PUBLISHED: 09-30-2014
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Multiple myeloma (MM) is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven MM-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or Cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of anti-myeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of MM patients exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in MM. Our study demonstrates that PDPK1 is a potent and an universally targetable signaling mediator in MM regardless of the types of cytogenetic/molecular profiles.
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Possible Involvement of Convergent Nociceptive Input to Medullary Dorsal Horn Neurons in Intraoral Hyperalgesia Following Peripheral Nerve Injury.
Cell. Mol. Neurobiol.
PUBLISHED: 09-09-2014
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Previous studies demonstrated that the number of c-Fos protein-like immunoreactive (c-Fos-IR) neurons in the medullary dorsal horn (MDH) evoked by noxious stimulation was increased after peripheral nerve injury, and such increase has been proposed to reflect the development of neuropathic pain state. The aim of this study was to examine the MDH for convergent collateral primary afferent input to second order neurons deafferented by peripheral nerve injury, and to explore a possibility of its contribution to the c-Fos hyperinducibility. Double immunofluorescence labeling for c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK) was performed to detect convergent synaptic input. c-Fos expression and the phosphorylation of ERK were induced by the intraoral application of capsaicin and by electrical stimulation of the inferior alveolar nerve (IAN), respectively. The number of c-Fos-IR neurons in the MDH induced by the intraoral application of capsaicin was increased after IAN injury, whereas the number of p-ERK immunoreactive neurons remained unchanged. The number of double-labeled neurons, that presumably received convergent primary afferent input from the lingual nerve and the IAN, was significantly increased after IAN injury. These results indicated that convergent primary nociceptive input through neighboring intact nerves may contribute to the c-Fos hyperinducibility in the MDH and the pathogenesis of neuropathic pain following trigeminal nerve injury.
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Assessment of intraoral mucosal pain induced by the application of capsaicin.
Arch. Oral Biol.
PUBLISHED: 08-23-2014
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To develop an objective method for assessing nociceptive behaviour in an animal model of capsaicin-induced intraoral pain. Changes in nociceptive responses were also examined after injury to the inferior alveolar nerve (IAN).
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Genetic analysis of Enterobius vermicularis isolated from a chimpanzee with lethal hemorrhagic colitis and pathology of the associated lesions.
Parasitol. Res.
PUBLISHED: 08-21-2014
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Human pinworms, Enterobius vermicularis, are normally recognized as minor pathogens. However, a fatal case of human pinworm infection has been reported in a nonhuman primate, a zoo reared chimpanzee. Here, we histopathologically examined the lesions in tissues from the deceased chimpanzee and genetically characterized the isolated worms to investigate the pathogenicity and determine the phylogeny. We identified ulcers deep in the submucosa where many parasites were found to have invaded the lamina propria mucosa or submucous tissue. An inflammatory reaction consisting mainly of neutrophils and lymphocytes but not eosinophils was observed around the parasites, and intense hemorrhage in the lamina propria was confirmed. The parasites were morphologically similar to E. vermicularis based on the shape of the copulatory spicules. Mitochondrial cytochrome c oxidase subunit 1 gene products were amplified from worm DNA by PCR and were genetically identified as E. vermicularis based on >98.7 % similarity of partial sequences. Phylogenetic analysis revealed that the sequences clustered together with other chimpanzee E. vermicularis isolates in a group which has been referred to as type C and which differs from human isolates (type A). The samples were negative for bacterial pathogens and Entamoeba histolytica indicating that E. vermicularis could be pathogenic in chimpanzees. Phylogenetic clustering of the isolates indicated that the parasite may be host specific.
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2-(4-Hydroxy-3-methoxyphenyl)-benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase CHIP.
Sci Rep
PUBLISHED: 07-16-2014
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Breast cancer is the most common malignancy among women and has poor survival and high recurrence rates for aggressive metastatic disease. Notably, triple-negative breast cancer (TNBC) is a highly aggressive cancer and there is no preferred agent for TNBC therapy. In this study, we show that a novel agent, 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole (YL-109), has ability to inhibit breast cancer cell growth and invasiveness in vitro and in vivo. In addition, YL-109 repressed the sphere-forming ability and the expression of stem cell markers in MDA-MB-231 mammosphere cultures. YL-109 increased the expression of carboxyl terminus of Hsp70-interacting protein (CHIP), which suppresses tumorigenic and metastatic potential of breast cancer cells by inhibiting the oncogenic pathway. YL-109 induced CHIP transcription because of the recruitment of the aryl hydrocarbon receptor (AhR) to upstream of CHIP gene in MDA-MB-231 cells. Consistently, the antitumor effects of YL-109 were depressed by CHIP or AhR knockdown in MDA-MB-231 cells. Taken together, our findings indicate that a novel agent YL-109 inhibits cell growth and metastatic potential by inducing CHIP expression through AhR signaling and reduces cancer stem cell properties in MDA-MB-231 cells. It suggests that YL-109 is a potential candidate for breast cancer therapy.
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Arm Volumetry Versus Upper Extremity Lymphedema Index: Validity of Upper Extremity Lymphedema Index for Body-Type Corrected Arm Volume Evaluation.
Ann Plast Surg
PUBLISHED: 07-09-2014
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Volumetry, measurement of extremity volume, is a commonly used method for upper extremity lymphedema (UEL) evaluation. However, comparison between different patients with different physiques is difficult with volumetry, because body-type difference greatly affects arm volume.
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Contralateral breast cancer adjacent to a fibroadenoma: report of a case.
J Nippon Med Sch
PUBLISHED: 07-08-2014
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A 64-year-old woman noticed a lump of the right breast and consulted our outpatient clinic. She had undergone multiple excisional biopsies of fibroadenomas in both breasts and mastectomy for invasive ductal carcinoma (IDC) of the left breast. After completing 5 years of treatment with adjuvant tamoxifen, she had undergone screening with annual physical examinations and occasional computed tomography. She was declared recurrence-free 13 years after breast cancer surgery, although lumps were detected in the right breast, probably due to fibroadenomas. Mammography, ultrasonography, and magnetic resonance imaging revealed that the lump was irregularly shaped, 2 cm in diameter, and adjacent to a fibroadenoma with macrocalcification. Two axillary lymph nodes were enlarged and suggestive of metastasis. A core needle biopsy revealed IDC of the right breast. She underwent a right partial mastectomy with axillary lymph node dissection. The IDC was 2 cm in diameter, of nuclear grade 2, and adjacent to a 0.7-cm fibroadenoma with a macrocalcification. The margins of the IDC close to the fibroadenoma were clearly demarcated by the fibrous capsule of the fibroadenoma. Four axillary lymph nodes were positive for metastasis. In the present case the presence of fibroadenoma might have interfered with the early detection of the contralateral IDC. The history of multiple excisions of fibroadenomas and mastectomy for breast cancer suggests an increased risk of contralateral breast cancer for the patient's entire life; therefore, regular annual follow-up, such as physical examinations and mammography, is recommended.
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Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta.
Hum. Mutat.
PUBLISHED: 07-02-2014
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Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal dominant inheritance; but, many autosomal recessive genes have been reported. We applied whole exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypo-functional nature of the two variants was demonstrated in a zebrafish assay. This article is protected by copyright. All rights reserved.
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Effect of occlusal rehabilitation on spatial memory and hippocampal neurons after long-term loss of molars in rats.
J Oral Rehabil
PUBLISHED: 05-11-2014
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Experimental loss of occlusal support caused by the extraction or grinding of molar teeth has been reported to foment the impairment of learning and memory in laboratory animals. The purpose of this study was to examine the effect of occlusal reconstruction after long-term loss of molars on spatial memory by using 8-arm radial maze and by assessing histopathological changes of neuron density in the hippocampus. Experimental dentures were inserted into the oral cavities of molarless rats to recover the occlusal support. Age-matched groups of control, molarless and denture-wearing rats were trained to perform the maze tasks. The difference of the error incidence in the maze task was evaluated between three groups. The difference of neuron density between three groups was also evaluated at the end of the maze task. Serum corticosterone levels were also measured to estimate the chronic stress, which could be caused by extraction, insertion of the experimental denture or any experimental procedure. The error incidence in the denture-wearing group was significantly higher than that of the control group, but significantly lower than that of the molarless group. Significant differences of neuron density were observed between three groups in each of the hippocampal CA1, CA3 and DG subfields. No significant difference of the serum corticosterone levels between three groups could be observed. From the results of this study, it was suggested that the recovery of occlusal support would bring amelioration of cognitive impairment concomitant with long period loss of molars in rats.
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Activation of AXL and antitumor effects of a monoclonal antibody to AXL in lung adenocarcinoma.
Anticancer Res.
PUBLISHED: 04-03-2014
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AXL (anexelekto) has been explored as a potential novel therapeutic target for non-small cell lung carcinoma (NSCLC) but its activation status has not been evaluated in NSCLC.
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An activation of LC3A-mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma.
J. Pathol.
PUBLISHED: 03-04-2014
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The development of therapeutic resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs, ie erlotinib or gefitinib) has been the major clinical problem when treating lung adenocarcinoma patients with these agents. However, its mechanisms have not necessarily been well studied to this date. Autophagy has been recently considered to play pivotal roles in escaping from the effects of anti-neoplastic agents. Therefore, in this study, we examined its roles in the development of resistance to EGFR-TKIs in lung adenocarcinoma. We first established erlotinib-resistant cell lines (PC9/ER) from parental PC9 cells by exposing the cells to erlotinib. In PC9/ER, autophagy-related LC3A expression came to be up-regulated and constitutive activation of LC3A-mediated autophagy became more pronounced through the process of acquiring therapeutic resistance. In addition, inhibition of LC3A or autophagy restores sensitivity to EGFR-TKIs in PC9/ER. LC3A was also activated at the transcriptional level in de novo resistant cells via demethylation of the MAP1LC3A gene. We then evaluated the status of LC3A in 169 lung adenocarcinoma patients using immunohistochemistry. LC3A immunoreactivity was only detected in carcinoma cells (89/169 patients), not in non-tumoural cells. In addition, LC3A immunoreactivity was significantly correlated with progression-free survival (p = 0.0039) and overall survival (p = 0.0040) of 35 patients treated with EGFR-TKIs. The results of our present study demonstrated that LC3A-mediated autophagy in carcinoma cells was involved in the development of resistance to EGFR-TKIs, and that LC3A could serve as a promising therapeutic target for overcoming resistance to EGFR-TKIs and a novel predictor of response to EGFR-TKIs in lung adenocarcinoma patients.
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Amelanotic malignant melanoma of unknown primary origin metastasizing to the bone marrow: a case report and review of the literature.
Intern. Med.
PUBLISHED: 02-18-2014
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We herein describe the case of a 77-year-old Japanese man who presented with progressive thrombocytopenia. No lymphadenopathies, bone lesions, hepatosplenomegaly or masses within any internal organs were detectable. Bone marrow smears revealed diffuse infiltration of large atypical cells morphologically resembling mature lymphoid neoplasms. A flow cytometric analysis showed that the tumor cells strongly expressed CD56 without myeloid or lymphoid antigens, suggesting that they were non-hematologic in origin. Ultimately, amelanotic malignant melanoma of unknown primary origin was diagnosed based on positive immunostaining for S100 proteins, HMB-45 and Melan-A. This case illustrates the usefulness of flow cytometric analyses for making such diagnoses. We also review the available literature on similar cases.
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Population pharmacokinetics of erlotinib in Japanese patients with advanced non-small cell lung cancer.
J Clin Pharm Ther
PUBLISHED: 02-17-2014
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This study aimed to elucidate the pharmacokinetics of erlotinib in Japanese patients with advanced non-small cell lung cancer (NSCLC) and to investigate the relationship between erlotinib exposure and the occurrence of interstitial lung disease (ILD)-like events.
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The role of non-enhanced angiography in toe tip transfer with small diameter pedicle.
Microsurgery
PUBLISHED: 02-12-2014
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Toe tip transfer allows functional and esthetic reconstruction of the lost fingertip, but it is still uncommon because identification and dissection of donor and recipient veins can be challenging. Nonenhanced angiography (NEA) is a device that emits infrared light at a wavelength of 850 nm, which is exclusively absorbed by hemoglobin. The light penetrates the bones and other soft tissues, effectively visualizing veins in real time. The aim of this report is to present the experience on the preoperative use of nonenhanced angiography for visualization of donor and recipient veins in toe tip transfers in a series of patients.
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Endogenous memory CD8 T cells directly mediate cardiac allograft rejection.
Am. J. Transplant.
PUBLISHED: 02-06-2014
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Differences in levels of environmentally induced memory T cells that cross-react with donor MHC molecules are postulated to account for the efficacy of allograft tolerance-inducing strategies in rodents versus their failure in nonhuman primates and human transplant patients. Strategies to study the impact of donor-reactive memory T cells on allografts in rodents have relied on the pretransplant induction of memory T cells cross-reactive with donor allogeneic MHC molecules through recipient viral infection, priming directly with donor antigen or adoptive transfer of donor antigen primed memory T cells. Each approach accelerates allograft rejection and confers resistance to tolerance induction, but also biases the T cell repertoire to strong donor reactivity. The ability of endogenous memory T cells within unprimed mice to directly reject an allograft is unknown. Here, we show a direct association between increased duration of cold ischemic allograft storage and numbers and enhanced functions of early graft infiltrating endogenous CD8 memory T cells. These T cells directly mediate rejection of allografts subjected to prolonged ischemia and this rejection is resistant to costimulatory blockade. These findings recapitulate the clinically significant impact of endogenous memory T cells with donor reactivity in a mouse transplant model in the absence of prior recipient priming.
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Over one-third of African-American MGUS and multiple myeloma patients are carriers of hyperphosphorylated paratarg-7, an autosomal dominantly inherited risk factor for MGUS/MM.
Int. J. Cancer
PUBLISHED: 02-04-2014
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As hyperphosphorylated paratarg-7 (pP-7) carrier state was shown to be the first molecularly defined autosomal dominantly inherited risk factor for monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma (MM) in a European population, the prevalence of pP-7 carrier state among African-Americans who have a significantly higher incidence of MGUS/MM is of interest. We therefore determined pP-7 carrier state and paraproteins with specificity for P-7 in African-American, European and Japanese patients with MGUS/MM and healthy controls. By isoelectric focusing and ELISA, a paratarg-7-specific paraprotein and the associated pP-7 carrier state was observed in 30/81 (37.0%) African-American, 42/252 (16.7%) European and 7/176 (4.0%) Japanese MGUS/MM patients (p < 0.001). A pP-7 carrier state was found in 11/100 (11.0%) African-American, 8/550 (1.5%) European and 1/278 (0.4%) Japanese healthy controls (p < 0.001), resulting in an odds ratio for MGUS/MM of 4.8 (p < 0.001) among African-American, 13.6 among European (p < 0.001) and 11.5 (p = 0.023) among Japanese carriers of pP-7. We conclude that pP-7 carriers are most prevalent among African-Americans, but a pP-7 carrier state is the strongest molecularly defined single risk factor for MGUS/MM known to date in all three ethnic groups. The high prevalence of pP-7 carriers among African-American patients emphasizes a predominant role of this genetic factor in the pathogenesis of these diseases. The large number of pP7 African-American patients and controls should facilitate the identification of the SNP or mutation underlying the pP-7 carrier state.
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Effects of JNK1/2 on the inflammation cytokine TNF-alpha-enhanced production of MMP-3 in human dental pulp fibroblast-like cells.
Int Endod J
PUBLISHED: 01-24-2014
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To investigate the effects of The c-Jun N-terminal kinase (JNK1/2) on the inflammation cytokine tumour necrosis factor-alpha (TNF-?)-enhanced production of matrix metalloproteinase-3 (MMP-3) in human dental pulp fibroblast-like cells (HPFs).
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Graft-derived CCL2 increases graft injury during antibody-mediated rejection of cardiac allografts.
Am. J. Transplant.
PUBLISHED: 01-17-2014
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The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5?/?/CD8?/? recipients rejected MHC-mismatched WT A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2?/? allografts induced low donor-reactive antibody titers and C4d deposition at Day 7 posttransplant. Decreased donor-reactive CD4 T cells producing interferon gamma were induced in response to A/J.CCL2?/? versus WT allografts. Consequently, A/J.CCL2?/? allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from WT allografts expressed high levels of IL-1? and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on Day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR.
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Modeling and simulation of orlistat to predict weight loss and weight maintenance in obesity patients.
Drug Metab. Pharmacokinet.
PUBLISHED: 01-14-2014
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Orlistat is used clinically worldwide as anti-obesity drug. It is a chemically synthesized hydrogenated derivative of lipstatin and is an inhibitor of gastric and pancreatic lipases. It has been found to reduce the absorption of dietary fat in the gastrointestinal tract. Modeling and simulation based on pharmacokinetic/pharmacodynamic analysis is becoming increasingly used in the design of clinical trials to assure that the trials are of high quality and are conducted efficiently. We developed a clinical trial simulation model for orlistat based on Phase III clinical study data. This innovative weight loss model includes the relationships between orlistat dose, changes in fecal fat excretion, and weight loss, and also incorporates a dropout function. The model guided the dose-finding strategy and allowed simulation of long-term clinical outcomes of orlistat.
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Design, synthesis, and biological activity of NCC149 derivatives as histone deacetylase 8-selective inhibitors.
ChemMedChem
PUBLISHED: 01-08-2014
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We recently discovered N-hydroxy-3-[1-(phenylthio)methyl-1H-1,2,3-triazol-4-yl]benzamide (NCC149) as a potent and selective histone deacetylase?8 (HDAC8) inhibitor from a 151-member triazole compound library using a click chemistry approach. In this work, we present a series of NCC149 derivatives bearing various aromatic linkers that were designed and synthesized as HDAC8-selective inhibitors. A series of in vitro assays were used to evaluate the newly synthesized compounds, four of which showed HDAC8 inhibitory activity similar to that of NCC149, and one of which displayed HDAC8 selectivity superior to that of NCC149. In addition, these top four compounds induced the increase of acetylated cohesin (an HDAC8 substrate) in HeLa cells in a dose-dependent manner, indicating inhibition of HDAC8 in the cells. While none of these compounds enhanced the acetylation of H3K9 (a substrate of HDAC1 and 2), only one compound refrained from increasing ?-tubulin acetylation, a substrate of HDAC6, indicating that this compound is more selective for HDAC8 than the other derivatives. Furthermore, this HDAC8-selective inhibitor suppressed the growth of T-cell lymphoma cells more potently than did NCC149. These findings are useful for the further development of HDAC8-selective inhibitors.
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Fabrication of single-crystalline microspheres with high sphericity from anisotropic materials.
Sci Rep
PUBLISHED: 01-03-2014
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Microspheres with high sphericity exhibit unique functionalities. In particular, their high symmetry makes them excellent omnidirectional optical resonators. As such perfect micrometre-sized spheres are known to be formed by surface tension, melt cooling is a popular method for fabricating microspheres. However, it is extremely difficult to produce crystalline microspheres using this method because their surfaces are normally faceted. Only microspheres of polymers, glass, or ceramics have been available, while single-crystalline microspheres, which should be useful in optical applications, have been awaiting successful production. Here we report the fabrication of single-crystalline semiconductor microspheres that have surfaces with atomic-level smoothness. These microspheres were formed by performing laser ablation in superfluid helium to create and moderately cool a melt of the anisotropic semiconductor material. This novel method provides cooling conditions that are exceptionally suited for the fabrication of single-crystalline microspheres. This finding opens a pathway for studying the hidden mechanism of anisotropy-free crystal growth and its applications.
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Highly frequent and enhanced injection site reaction induced by peripheral venous injection of fosaprepitant in anthracycline-treated patients.
J Cancer
PUBLISHED: 01-01-2014
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Fosaprepitant-associated injection site reaction (ISR) has been reported in patients treated with cisplatin, an irritant drug. We conducted this retrospective study to clarify the incidence and symptoms of fosaprepitant-associated ISR in patients treated with anthracycline.
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Identification of a Novel Compound That Suppresses Breast Cancer Invasiveness by Inhibiting Transforming Growth Factor-? Signaling via Estrogen Receptor ?.
J Cancer
PUBLISHED: 01-01-2014
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Breast cancer is the most frequently diagnosed cancer and the leading cause of death by cancer among females worldwide. An overwhelming majority of these deaths is because of metastasis. Estrogen stimulates and promotes growth of breast tumors, whereas transforming growth factor-beta (TGF-?) signaling promotes invasion and metastasis. We previously reported that estrogen and estrogen receptor alpha (ER?) suppressed breast cancer metastasis by inhibiting TGF-? signaling, whereas antiestrogens that suppress breast cancer growth, such as the selective ER modulator tamoxifen (TAM) or the pure antiestrogen fulvestrant (ICI 182,780), cannot suppress TGF-? signaling or breast cancer invasiveness. Therefore, we predicted that a compound that inhibits TGF-? signaling but does not facilitate ER? signaling would be ideal for suppressing breast cancer invasiveness and growth. In the present study, we identified an ideal candidate compound, N-23. Like estrogen, N-23 strongly decreased expression of TGF-?/Smad target gene plasminogen activator inhibitor-1 (PAI-1), but it did not increase the expression of ER? target gene pS2. While estrogen decreased the levels of phosphorylated Smad2 and Smad3, N-23 had no effect. In addition, TGF-?-dependent recruitment of Smad3 to the PAI-1 gene promoter was inhibited in the presence of estrogen or N-23. We also investigated the effects of N-23 on proliferation, migration, and invasion of breast cancer cells. In contrast to estrogen, N-23 inhibited the cellular proliferation of breast cancer cells. Moreover, we showed that N-23 suppressed the migration and invasion of breast cancer cells to the same extent as by estrogen. Taken together, our findings indicate that N-23 may be a candidate compound that is effective in inhibiting breast cancer progression.
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HTLV-1 bZIP Factor-Specific CD4 T Cell Responses in Adult T Cell Leukemia/Lymphoma Patients After Allogeneic Hematopoietic Stem Cell Transplantation.
J. Immunol.
PUBLISHED: 12-20-2013
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We document human T lymphotropic virus type 1 (HTLV-1) bZIP factor (HBZ)-specific CD4 T cell responses in an adult T cell leukemia/lymphoma (ATL) patient after allogeneic hematopoietic stem cell transplantation (HCT) and identified a novel HLA-DRB1*15:01-restricted HBZ-derived naturally presented minimum epitope sequence, RRRAEKKAADVA (HBZ114-125). This peptide was also presented on HLA-DRB1*15:02, recognized by CD4 T cells. Notably, HBZ-specific CD4 T cell responses were only observed in ATL patients after allogeneic HCT (4 of 9 patients) and not in nontransplanted ATL patients (0 of 10 patients) or in asymptomatic HTLV-1 carriers (0 of 10 carriers). In addition, in one acute-type patient, HBZ-specific CD4 T cell responses were absent in complete remission before HCT, but they became detectable after allogeneic HCT. We surmise that HTLV-1 transmission from mothers to infants through breast milk in early life induces tolerance to HBZ and results in insufficient HBZ-specific T cell responses in HTLV-1 asymptomatic carriers or ATL patients. In contrast, after allogeneic HCT, the reconstituted immune system from donor-derived cells can recognize virus protein HBZ as foreign, and HBZ-specific immune responses are provoked that contribute to the graft-versus-HTLV-1 effect.
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Reduced plasma glucose by asparagine synthetase knockdown in the mouse liver.
Biol. Pharm. Bull.
PUBLISHED: 12-03-2013
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Expression of the asparagine synthetase gene is dependent on extracellular glucose concentration. This gene was knocked-down in livers of male Balb/c mice by a hydrodynamic tail vein injection of small interfering RNA (siRNA) against the gene. This knockdown resulted in a significant decrease in plasma glucose concentration. These results suggested that asparagine synthetase is a novel protein that regulates plasma glucose levels.
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Antitumor effects of bevacizumab in a microenvironment-dependent human adult T-cell leukemia/lymphoma mouse model.
Eur. J. Haematol.
PUBLISHED: 10-29-2013
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The objective of the present study was to evaluate the therapeutic potential of bevacizumab with or without systemic chemotherapy for adult T-cell leukemia/lymphoma (ATL), and clarify the significance of angiogenesis for ATL pathogenesis.
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Indocyanine green velocity: lymph transportation capacity deterioration with progression of lymphedema.
Ann Plast Surg
PUBLISHED: 10-16-2013
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Lymph transportation capacity is a critical function maintaining fluid circulation. After pelvic cancer treatments, lymph obstruction at the pelvic region leads to abnormal lymph circulation, resulting in lymph pump dysfunction. Besides lymph circulation, lymph pump function is important for lymphedema evaluation. We assessed and analyzed lymph transportation capacity of secondary lower extremity lymphedema patients using indocyanine green (ICG) lymphography according to corresponding severity stage. Indocyanine green velocity and transit time could evaluate lymph pump function; ICG velocity decreases and transit time increases as the lymphedema severity stage progresses. Measurement of ICG velocity required 5 minutes after the dye injection, whereas that of transit time took more than 1 hour in severe cases. Indocyanine green velocity can be easily obtained and is recommended for evaluation of lymph pump function compared with transit time. Dynamic ICG lymphography, which evaluates both lymph pump function and circulation, plays an important role in comprehensive assessment of lymphedema pathophysiology.
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Hemoglobin Receptor Protein from Porphyromonas gingivalis Induces Interleukin-8 Production in Human Gingival Epithelial Cells through Stimulation of the Mitogen-Activated Protein Kinase and NF-?B Signal Transduction Pathways.
Infect. Immun.
PUBLISHED: 10-14-2013
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Periodontitis is an inflammatory disease of polymicrobial origin affecting the tissues supporting the tooth. The oral anaerobic bacterium Porphyromonas gingivalis, which is implicated as an important pathogen for chronic periodontitis, triggers a series of host inflammatory responses that promote the destruction of periodontal tissues. Among the virulence factors of P. gingivalis, hemoglobin receptor protein (HbR) is a major protein found in culture supernatants. In this study, we investigated the roles of HbR in the production of inflammatory mediators. We found that HbR induced interleukin-8 (IL-8) production in the human gingival epithelial cell line Ca9-22. p38 mitogen-activated protein kinase (MAPK) and extracellular signal-related kinase 1/2 (Erk1/2) were activated in HbR-stimulated Ca9-22 cells. Inhibitors of p38 MAPK (SB203580) and Erk1/2 (PD98059) blocked HbR-induced IL-8 production. Additionally, HbR stimulated the translocation of NF-?B-p65 to the nucleus, consistent with enhancement of IL-8 expression by activation of the NF-?B pathway. In addition, small interfering RNA (siRNA) targeting activating transcription factor 2 (ATF-2) or cyclic AMP-response element-binding protein (CREB) inhibited HbR-induced IL-8 production. Moreover, pretreatment with SB203580 and PD98059 reduced HbR-induced phosphorylation of CREB and ATF-2, respectively. Combined pretreatment with an inhibitor of NF-?B (BAY11-7082) and SB203580 was more efficient in inhibiting the ability of HbR to induce IL-8 production than pretreatment with either BAY11-7082 or SB203580 alone. Thus, in Ca9-22 cells, the direct activation of p38 MAPK and Erk1/2 by HbR caused the activation of the transcription factors ATF-2, CREB, and NF-?B, thus resulting in the induction of IL-8 production.
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Assessment of speech production with dentures by electromagnetic articulography.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 10-11-2013
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This report investigates the use of electromagnetic articulography (EMA) to compare basic speech patterns between a patient with traditional dentures to those of a normally dentate person. The goal is to assess the efficacy of traditional dentures in order to generate clinical data and works towards the improvement of denture design. Kinematic and acoustic data were acquired for these two subjects using a variety of repetitive vowel-consonant-vowel tasks. Spatiotemporal parameters indicating dynamic properties of the tongue blade and jaw movements, and timing coordination of the movements between them and with the output acoustic signal, were measured and compared within and between the participants. The results show significant differences in both spatial and temporal patterns and variation between individual tasks within each subjects data, as well as a difference in the two subjects performance of the same task (cross-subject) for select calculated kinematic and latency parameters. It is concluded that there is more variation in spatiotemporal parameters in speech patterns for patients with dentures than without; in particular, latencies of the tongue blade and jaw movements and acoustic landmarks of the consonants, show strategies of movements timing coordination, typical of the speaker with denture.
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[Implementation of acute stroke rehabilitation services in our hospital -comparison between the years 2010 and 2000-].
J. UOEH
PUBLISHED: 10-01-2013
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We retrospectively compared the stroke rehabilitation services in our hospital in 2010 with those in 2000. The severity of strokes in 2010 was worse than that in 2000. The period between the onset of stroke and beginning of physical therapy was shortened from 11.3 days to 4.0 days, and the period between prescription and beginning of physical therapy was shortened from 1.1 days to 0.2 days. We consider that two reasons for these changes were that requests to the department of rehabilitation came at earlier stages in the development of symptoms and that we could shift chronic rehabilitation services to acute rehabilitation services due to an increase in the number of physical therapists. Introducing the electronic medical record system might also have been efficient for these changes.
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A comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in Japan: Are Japanese phase I studies still needed?
J Clin Pharmacol
PUBLISHED: 09-26-2013
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Ethnic evaluation of the pharmacokinetics and safety of new drugs is required in Japan before implementing bridging or joining global studies. As therapeutic monoclonal antibodies (mAbs) show limited ethnic differences, their pharmacokinetics and safety in Japanese individuals could be estimated from prior non-Japanese studies. Therefore, there is potential to re-evaluate the development program for mAbs in Japan. We reviewed the pharmacokinetics of mAbs approved in Japan. Although some differences had been observed in pharmacokinetics of mAbs between Japanese and non-Japanese populations (mainly Caucasians), these differences were attributed to differences of body weight and/or antigen levels. Moreover, the influential factors can be estimated without conducting regional pharmacokinetic/safety studies. The pharmacokinetics of some mAbs is presumably non-linear and show differences between healthy volunteers and patients because of differences in antigen levels. However, for 10/24 mAbs approved in Japan, Japanese healthy volunteer studies were conducted before the patient studies. Additionally, for the mAbs that showed ethnic differences in pharmacokinetics, the doses selected in subsequent patient studies were the same as the doses approved in the United States. In this review, we discuss new drug development strategies in various regions, and assess the need for regional pharmacokinetics/safety studies before joining global studies.
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Comparison of indocyanine green lymphographic findings with the conditions of collecting lymphatic vessels of limbs in patients with lymphedema.
Plast. Reconstr. Surg.
PUBLISHED: 09-06-2013
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The authors investigated the relationship between findings from indocyanine green lymphography and the condition of lymphatics according to the Normal, Ectasis, Contraction, Sclerosis Type classifications observed in each area during surgery.
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Solution structure of an intramolecular (3 + 1) human telomeric G-quadruplex bound to a telomestatin derivative.
J. Am. Chem. Soc.
PUBLISHED: 08-27-2013
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Guanine-rich human telomeric DNA can adopt secondary structures known as G-quadruplexes, which can be targeted by small molecules to achieve anticancer effects. So far, the structural information on complexes between human telomeric DNA and ligands is limited to the parallel G-quadruplex conformation, despite the high structural polymorphism of human telomeric G-quadruplexes. No structure has been yet resolved for the complex with telomestatin, one of the most promising G-quadruplex-targeting anticancer drug candidates. Here we present the first high-resolution structure of the complex between an intramolecular (3 + 1) human telomeric G-quadruplex and a telomestatin derivative, the macrocyclic hexaoxazole L2H2-6M(2)OTD. This compound is observed to interact with the G-quadruplex through ?-stacking and electrostatic interactions. This structural information provides a platform for the design of topology-specific G-quadruplex-targeting compounds and is valuable for the development of new potent anticancer drugs.
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Macrocyclic polyoxazoles as g-quadruplex ligands.
Chem Rec
PUBLISHED: 07-31-2013
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This review deals with recent progress in the synthesis and evaluation of our telomestatin-inspired macrocyclic polyoxazoles as G-quadruplex (G4) ligands. The hexaoxazole derivatives (6OTDs) interact with and stabilize G4-forming oligonucleotides, depending upon the character of the side chain functional groups. Cationic functional groups are particularly effective due to their secondary interaction with phosphate in the DNA backbone. On the other hand, heptaoxazole derivatives (7OTDs) showed potent G4-binding and stabilization activity regardless of the functional groups on the side chain. A caged G4 ligand, Y2Nv2-6OTD (7), and a fluorescent G4 ligand, L1BOD-7OTD (13), have been synthesized.
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Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma.
Leuk. Res.
PUBLISHED: 07-29-2013
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CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients.
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Fluorescent-Ligand-Mediated Screening of G-Quadruplex Structures Using a DNA Microarray.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 06-21-2013
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Light up, G-quadruplexes! A fast high-throughput screening for the discovery of novel G-quadruplex-forming oligonucleotides (GFOs) has been developed. By using a fluorescent G-quadruplex ligand and a DNA microarray, 1998 novel GFO candidates in CpG islands were disclosed. (CpG=cytosine-phosphate-guanosine).
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Selective optical assembly of highly uniform nanoparticles by doughnut-shaped beams.
Sci Rep
PUBLISHED: 06-19-2013
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A highly efficient natural light-harvesting antenna has a ring-like structure consisting of dye molecules whose absorption band changes through selective evolutionary processes driven by external stimuli, i.e., sunlight depending on its territory and thermal fluctuations. Inspired by this fact, here, we experimentally and theoretically demonstrate the selective assembling of ring-like arrangements of many silver nanorods with particular shapes and orientations onto a substrate by the light-induced force of doughnut beams with different colours (wavelengths) and polarizations in conjunction with thermal fluctuations at room temperature. Furthermore, the majority of nanorods are electromagnetically coupled to form a prominent red-shifted collective mode of localized surface plasmons resonant with the wavelength of the irradiated light, where a spectral broadening also appears for the efficient broadband optical response. The discovered principle is a promising route for "bio-inspired selective optical assembly" of various nanomaterials that can be used in the wide field of nanotechnology.
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Effect of geometry and microstructure of honeycomb TCP scaffolds on bone regeneration.
J Biomed Mater Res A
PUBLISHED: 06-03-2013
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In recent years, artificial biological materials have been commonly used for the treatment of bone tissue defects caused by trauma, tumors, or surgical stress. Although tricalcium phosphate (TCP) is a promising absorbent bone tissue reconstruction biomaterial, it has been reported that its biocompatibility and osteoconductivity depend on its preparation method and sintering temperature. In addition, although it is thought that the microenvironment produced by the extracellular matrix plays an important role in cell growth and differentiation, there have been few studies on how the geometric structure of artificial biological materials affects cells. In the present study, a new honeycomb TCP scaffold containing through-holes with diameters of 300 µm has been developed. The influence of the sintering temperature on the crystal structure and material properties of the honeycomb TCP scaffold was investigated using scanning electron microscopy and X-ray diffraction. Its biocompatibility and osteoconductivity were also evaluated by implantation into experimental animals. It was found that a ?-TCP scaffold sintered at 1200°C exhibited high biocompatibility and osteoconductivity, and when it was loaded with BMP-2, it exhibited both osteoconductivity and osteoinductivity, promoting rapid bone formation in both ectopic and orthotopic areas. It is thus a highly promising bone reconstruction material that is expected to find clinical applications. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
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Versatility of lateral cutaneous branches of intercostal vessels and nerves: anatomical study and clinical application.
J Plast Reconstr Aesthet Surg
PUBLISHED: 06-03-2013
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The use of the intercostal artery perforator (ICAP) flap has recently become popular in reconstructions of the breast, upper arm and trunk. Lateral cutaneous branches (LCBs) are a group of the ICAPs that penetrate the fascia near the middle axillary line. However, reports on its precise anatomy and clinical applications are quite limited. We performed an anatomical study of LCBs using cadavers. Based on the findings, we developed novel clinical application methods as follows: (1) sensate superficial circumflex iliac perforator (SCIP) flap, (2) supercharged SCIP flap, (3) ICAP-based propeller flap (IBPF) and (4) free ICAP flap based on LCB. LCBs have the following advantages: (1) Long pedicles can be obtained in the supine position without risk of pneumothorax. (2) The neurovascular bundle is consistently available, allowing elevation of sensate flaps. (3) Donor-site morbidity is low. Therefore, we believe that LCBs offer a versatile option in reconstructive surgery.
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Autologous Tax-specific CTL therapy in a primary adult T cell leukemia/lymphoma cell-bearing NOD/Shi-scid, IL-2R?null mouse model.
J. Immunol.
PUBLISHED: 06-03-2013
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We expanded human T-lymphotropic virus type 1 Tax-specific CTL in vitro from PBMC of three individual adult T cell leukemia/lymphoma (ATL) patients and assessed their therapeutic potential in an in vivo model using NOG mice bearing primary ATL cells from the respective three patients (ATL/NOG). In these mice established with cells from a chronic-type patient, treatment by i.p. injection of autologous Tax-CTL resulted in greater infiltration of CD8-positive T cells into each ATL lesion. This was associated with a significant decrease of ATL cell infiltration into blood, spleen, and liver. Tax-CTL treatment also significantly decreased human soluble IL-2R concentrations in the sera. In another group of ATL/NOG mice, Tax-CTL treatment led to a significant prolongation of survival time. These findings show that Tax-CTL can infiltrate the tumor site, recognize, and kill autologous ATL cells in mice in vivo. In ATL/NOG mice with cells from an acute-type patient, whose postchemotherapeutic remission continued for >18 mo, antitumor efficacy of adoptive Tax-CTL therapy was also observed. However, in ATL/NOG mice from a different acute-type patient, whose ATL relapsed after 6 mo of remission, no efficacy was observed. Thus, although the therapeutic effects were different for different ATL patients, to the best of our knowledge, this is the first report that adoptive therapy with Ag-specific CTL expanded from a cancer patient confers antitumor effects, leading to significant survival benefit for autologous primary cancer cell-bearing mice in vivo. The present study contributes to research on adoptive CTL therapy, which should be applicable to several types of cancer.
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Transient lymphopenia breaks costimulatory blockade-based peripheral tolerance and initiates cardiac allograft rejection.
Am. J. Transplant.
PUBLISHED: 05-06-2013
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Lymphopenia is induced by lymphoablative therapies and chronic viral infections. We assessed the impact of lymphopenia on cardiac allograft survival in recipients conditioned with peritransplant costimulatory blockade (CB) to promote long-term graft acceptance. After vascularized MHC-mismatched heterotopic heart grafts were stably accepted through CB, lymphopenia was induced on day 60 posttransplant by 6.5 Gy irradiation or by administration of anti-CD4 plus anti-CD8 mAb. Long-term surviving allografts were gradually rejected after lymphodepletion (MST = 74 ± 5 days postirradiation). Histological analyses indicated signs of severe rejection in allografts following lymphodepletion, including mononuclear cell infiltration and obliterative vasculopathy. Lymphodepletion of CB conditioned recipients induced increases in CD44(high) effector/memory T cells in lymphatic organs and strong recovery of donor-reactive T cell responses, indicating lymphopenia-induced proliferation (LIP) and donor alloimmune responses occurring in the host. T regulatory (CD4(+) Foxp(3+)) cell and B cell numbers as well as donor-specific antibody titers also increased during allograft rejection in CB conditioned recipients given lymphodepletion. These observations suggest that allograft rejection following partial lymphocyte depletion is mediated by LIP of donor-reactive memory T cells. As lymphopenia may cause unexpected rejection of stable allografts, adequate strategies must be developed to control T cell proliferation and differentiation during lymphopenia.
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Toluene Exposure Leads to a Change in Expression Patterns of ? Defensins in the Mouse Tracheal Epithelium.
J Toxicol Pathol
PUBLISHED: 04-22-2013
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Defensins are generally implicated in the quick resistance of epithelial surfaces to microbials; however, recent reports have indicated that defensins also have unknown purposes in relation to noninfectious diseases. In this study, the localization patterns of anti-microbial peptides, ? defensins (BDs), in the tracheal epithelium of male C3H mice under exposure to toluene were analyzed by immunohistochemistry. Mice were exposed one to ten times to toluene for 30 min by nose-only inhalation. Expression of BDs was revealed by immunohistochemistry in serial sections of trachea after the final exposure. Expression of BD-1 was usually observed at almost the same levels in all exposure groups, and expression of BD-2 was observed in the control group; however, the signals for BD-2 decreased gradually with frequency of exposure. In the group exposed ten times, expression of BD-2 decreased to far lower than that of the control group. No expression of BD-3 was detected in any groups. Interestingly, expression of BD-4 increased to the maximum in the group exposed four times and decreased to a level lower than that of the control in the group exposed ten times. The results of the present study indicated that toluene gas might change the expression pattern of BDs in the tracheal epithelial cells. The oscillation of expression of BD-4 was quite characteristic and might contribute to morphological damage in on the epithelial cells.
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Clinical and Radiographic Features of the Autosomal Recessive form of Brachyolmia Caused by PAPSS2 Mutations.
Hum. Mutat.
PUBLISHED: 04-06-2013
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Brachyolmia is a heterogeneous skeletal dysplasia characterized by generalized platyspondyly without significant long-bone abnormalities. Based on the mode of inheritance and radiographic features, at least three types of brachyolmia have been postulated. We recently identified an autosomal recessive form of brachyolmia that is caused by loss-of-function mutations of PAPSS2, the gene encoding PAPS (3-phosphoadenosine 5-phosphosulfate) synthase 2. To understand brachyolmia caused by PAPSS2 mutations (PAPSS2-brachyolmia), we extended our PAPSS2 mutation analysis to 13 patients from 10 families and identified homozygous or compound heterozygous mutations in all. Nine different mutations were found: three splice donor-site mutations, three missense mutations, and three insertion or deletion mutations within coding regions. In vitro enzyme assays showed that the missense mutations were also loss-of-function mutations. Phenotypic characteristics of PAPSS2-brachyolmia include short-trunk short stature, normal intelligence and facies, spinal deformity, and broad proximal interphalangeal joints. Radiographic features include platyspondyly with rectangular vertebral bodies and irregular end plates, broad ilia, metaphyseal changes of the proximal femur, including short femoral neck and striation, and dysplasia of the short tubular bones. PAPSS2-brachyolmia includes phenotypes of the conventional clinical concept of brachyolmia, the Hobaek and Toledo types, and is associated with abnormal androgen metabolism.
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Exome sequencing identifies a novel INPPL1 mutation in opsismodysplasia.
J. Hum. Genet.
PUBLISHED: 04-04-2013
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Opsismodysplasia is an autosomal recessive skeletal disorder characterized by facial dysmorphism, micromelia, platyspondyly and retarded bone maturation. Recently, mutations in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1) are found in several families with opsismodysplasia by a homozygosity mapping, followed by whole genome sequencing. We performed an exome sequencing in two unrelated Japanese families with opsismodysplasia and identified a novel INPPL1 mutation, c.1960_1962delGAG, in one family. The mutation is predicted to result in an in-frame deletion (p.E654del) within the central catalytic 5-phosphate domain. Our results further support that INPPL1 is the disease gene for opsismodysplasia and that opsismodysplasia has genetic heterogeneity.
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Phase I/II study of bortezomib-melphalan-prednisolone for previously untreated Japanese patients with multiple myeloma.
Cancer Sci.
PUBLISHED: 03-26-2013
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This phase I/II study was conducted to evaluate the safety and efficacy of bortezomib-melphalan-prednisolone in Japanese patients with previously untreated multiple myeloma who are ineligible for hematopoietic stem cell transplantation. One hundred and one patients were enrolled, and 99 patients received up to nine 6-week cycles of bortezomib (0.7/1.0/1.3 mg/m²) on days 1, 4, 8, 11, 22, 25, 29, and 32 in cycles 1-4 and on days 1, 8, 22, and 29 in cycles 5-9, with melphalan (9 mg/m²) and prednisolone (60 mg/m²) on days 1-4 of each cycle. The recommended dose was determined in the phase I portion, and the overall response rate and safety of bortezomib-melphalan-prednisolone at the recommended dose were assessed in the phase II portion. The recommended dose of bortezomib was determined to be 1.3 mg/m². Grade 3 or higher non-hematological adverse events included diarrhea (12%) and peripheral neuropathy (10%); grade 4 hematological adverse events included lymphopenia (41%), neutropenia (30%), and thrombocytopenia (22%). Eleven patients had lung injury associated with bortezomib; two had grade 3 disease, and the other nine had grade 1 or 2 disease. Of the 86 patients treated with 1.3-mg/m² bortezomib in phases I and II, the median number of treatment cycles was 4.5, and the overall response rate was 70% (95% confidence interval: 59-79%). Bortezomib-melphalan-prednisolone with 1.3-mg/m² bortezomib was considered to be tolerable and effective in Japanese patients with previously untreated multiple myeloma. However, further investigation is needed to refine the administration schedule.
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Steroid sulphatase and oestrogen sulphotransferase in human non-small-cell lung carcinoma.
Br. J. Cancer
PUBLISHED: 03-26-2013
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Steroid sulphatase (STS) is one of the steroid-metabolising enzymes involved in desulphating inactive steroid sulphates and oestrogen sulphotransferase (EST) sulphates active oestrogen. The roles of both STS and EST have not been examined in oestrogen-dependent non-small-cell lung cancer (NSCLC).
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Phytohemagglutinin-induced IL2 mRNA in whole blood can predict bortezomib-induced peripheral neuropathy for multiple myeloma patients.
Blood Cancer J
PUBLISHED: 03-13-2013
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The proteasome inhibitor bortezomib has revolutionized the treatment of multiple myeloma. However, bortezomib-induced peripheral neuropathy (BiPN) is a serious complication that compromises clinical outcome. If patients with a risk of developing BiPN could be predicted, physicians might prefer weekly, reduced-dose, or subcutaneous approaches. To seek biomarkers for BiPN, we conducted a multicenter prospective study using a simple and unique system. Multiple myeloma patients received twice-weekly or weekly 1.3?mg/m(2) bortezomib intravenously, and a 2-ml sample of whole blood was obtained before treatment and 2-3 days and 1-3 weeks after the first dose. Induction of gene expression was then quantified by real-time PCR. Of a total of 64 enrolled patients, 53 patient samples qualified for mRNA analysis. The BiPN grade was associated with phytohemagglutinin-induced IL2, IFNG and TNFSF2, as well as with lipopolysaccharide-induced IL6 levels. More importantly, of the 19 patients showing a ?3-fold increase in phytohemagglutinin-induced IL2, 14 did not suffer from BiPN (73.7% prediction), whereas of the 34 patients with a <3-fold increase, 23 experienced BiPN (67.6% prediction). Therefore, we concluded that pretreatment of phytohemagglutinin-induced IL2 mRNA levels in whole blood serve as a promising biomarker for predicting BiPN, and this finding warrants validation in a larger study.
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Evaluation of the interaction between long telomeric DNA and macrocyclic hexaoxazole (6OTD) dimer of a G-quadruplex ligand.
Molecules
PUBLISHED: 03-12-2013
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Macrocyclic hexaoxazole dimer of L2H2-6OTD-dimer (3) was newly synthesized as a telomeric G-quadruplex (G4) ligand, and interaction with long telomeric DNAs telo48, 72, and 96 was evaluated by means of electrophoresis mobility shift assay, CD spectra analysis, and CD melting experiments. The L2H2-6OTD-dimer (3) interacted with the long telomeric DNAs by inducing anti-parallel type G4 structure of each unit of 24 bases, i.e., (TTAGGG)? sequences. Dimer 3 stabilizes long telomeric DNAs more efficiently than the corresponding monomer of L2H2-6OTD (2). It showed potent inhibitory activity against telomerase, with an IC?? value of 7.5 nm.
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Population pharmacokinetic-pharmacodynamic modelling and simulation of neutropenia induced by TP300, a novel topoisomerase I inhibitor.
J. Pharm. Pharmacol.
PUBLISHED: 03-06-2013
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TP300 is a novel topoisomerase I inhibitor with neutropenia as a significant toxicity. We developed and evaluated a pharmacokinetic-pharmacodynamic (PK-PD) model, using data from Phase I and II trials to predict neutrophil decrease in patients treated with TP300.
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Ectopic expression of Ptf1a induces spinal defects, urogenital defects, and anorectal malformations in Danforths short tail mice.
PLoS Genet.
PUBLISHED: 02-21-2013
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Danforths short tail (Sd) is a semidominant mutation on mouse chromosome 2, characterized by spinal defects, urogenital defects, and anorectal malformations. However, the gene responsible for the Sd phenotype was unknown. In this study, we identified the molecular basis of the Sd mutation. By positional cloning, we identified the insertion of an early transposon in the Sd candidate locus approximately 12-kb upstream of Ptf1a. We found that insertion of the transposon caused overexpression of three neighboring genes, Gm13344, Gm13336, and Ptf1a, in Sd mutant embryos and that the Sd phenotype was not caused by disruption of an as-yet-unknown gene in the candidate locus. Using multiple knockout and knock-in mouse models, we demonstrated that misexpression of Ptf1a, but not of Gm13344 or Gm13336, in the notochord, hindgut, cloaca, and mesonephros was sufficient to replicate the Sd phenotype. The ectopic expression of Ptf1a in the caudal embryo resulted in attenuated expression of Cdx2 and its downstream target genes T, Wnt3a, and Cyp26a1; we conclude that this is the molecular basis of the Sd phenotype. Analysis of Sd mutant mice will provide insight into the development of the spinal column, anus, and kidney.
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Endogenous memory CD8 T cells are activated within cardiac allografts without mediating rejection.
Am. J. Transplant.
PUBLISHED: 02-13-2013
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Endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts within 12-24 h posttransplant in mice and are activated to proliferate and produce IFN-?. To more accurately assess the graft injury directly imposed by these endogenous memory CD8 T cells, we took advantage of the ability of anti-LFA-1 mAb given to allograft recipients on days 3 and 4 posttransplant to inhibit the generation of primary effector T cells. When compared to grafts from IgG-treated recipients on day 7 posttransplant, allografts from anti-LFA-1 mAb-treated recipients had increased numbers of CD8 T cells but these grafts had marked decreases in expression levels of mRNA encoding effector mediators associated with graft injury and decreases in donor-reactive CD8 T cells producing IFN-?. Despite this decreased activity within the allograft, CD8 T cells in allografts from recipients treated with anti-LFA-1 mAb continued to proliferate up to day 7 posttransplant and did not upregulate expression of the exhaustion marker LAG-3 but did have decreased expression of ICOS. These results indicate that endogenous memory CD8 T cells infiltrate and proliferate in cardiac allografts in mice but do not express sufficient levels of functions to mediate overt graft injury and acute rejection.
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The effect of lymphatico-venous anastomosis for an intractable ulcer at the lower leg in a marked obese patient.
Microsurgery
PUBLISHED: 02-11-2013
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Secondary lymphedema occurs after trauma, cancer surgery, or obesity, and wounds in lymphedema can easily become intractable. We report positive results using lymphatico-venous anastomosis (LVA) to treat a post-traumatic lymph fistula and an intractable ulcer in a severely obese patient. A 41-year-old male (BMI 51.8), one year prior, had a traffic injury, and had an 18-cm contusion in his right leg. Six months later, lymph leakage in a 14 cm?×?8 cm region and a 5 cm?×?3 cm skin ulcer occurred in the center of the wound. We made a diagnosis of lymphedema resulting from obesity, accompanied with lymphorrhea and intractable ulcer. He was unable to reach his legs owing to obesity, making complex physical therapy impossible. We performed LVA under local anesthesia. The lymphorrhea healed 2 weeks after the operation and had not recurred 3 months after the operation. The leg lymphedema improved after the surgery without the compression therapy. In cases of intractable ulcers, suspected of being caused by lymphostasis, treatments indicated for lymphedema, for example LVA, may possibly allow satisfactory wound healing. © 2013 Wiley Periodicals, Inc. Microsurgery 34:64-67, 2014.
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Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders.
Am. J. Hum. Genet.
PUBLISHED: 02-01-2013
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Proteoglycans (PGs) are a major component of the extracellular matrix in many tissues and function as structural and regulatory molecules. PGs are composed of core proteins and glycosaminoglycan (GAG) side chains. The biosynthesis of GAGs starts with the linker region that consists of four sugar residues and is followed by repeating disaccharide units. By exome sequencing, we found that B3GALT6 encoding an enzyme involved in the biosynthesis of the GAG linker region is responsible for a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1). B3GALT6 loss-of-function mutations were found in individuals with SEMD-JL1 from seven families. In a subsequent candidate gene study based on the phenotypic similarity, we found that B3GALT6 is also responsible for a connective tissue disease, Ehlers-Danlos syndrome (progeroid form). Recessive loss-of-function mutations in B3GALT6 result in a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation, and spinal deformity. The pleiotropic phenotypes of the disorders indicate that B3GALT6 plays a critical role in a wide range of biological processes in various tissues, including skin, bone, cartilage, tendon, and ligament.
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Stevens-Johnson Syndrome associated with mogamulizumab treatment of adult T-cell leukemia / lymphoma.
Cancer Sci.
PUBLISHED: 01-21-2013
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We report an adult T-cell leukemia/lymphoma patient suffering from Stevens-Johnson Syndrome (SJS) during mogamulizumab (humanized anti-CCR4 monoclonal antibody) treatment. There was a durable significant reduction of the CD4(+) CD25(high) FOXP3(+) regulatory T (Treg) cell subset in the patients PBMC, and the affected inflamed skin almost completely lacked FOXP3-positive cells. This implies an association between reduction of the Treg subset by mogamulizimab and occurrence of SJS. The present case should contribute not only to our understanding of human pathology resulting from therapeutic depletion of Treg cells, but also alert us to the possibility of immune-related severe adverse events such as SJS when using mogamulizumab. We are currently conducting a clinical trial of mogamulizumab for CCR4-negative solid cancers (UMIN000010050), specifically aiming to deplete Treg cells.
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A two-stage operation for thoracic esophageal cancer: esophagectomy and subsequent reconstruction by a free jejunal flap.
Surg. Today
PUBLISHED: 01-18-2013
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When the stomach is unavailable for esophageal reconstruction due to previous gastrectomy or synchronous gastric cancer, a pedicled jejunum or colon, with or without vascular supercharge, has been the alternative. However, these reconstructions are not free from severe complications, such as necrosis. We have introduced a new surgical technique for delayed esophageal reconstruction using a free jejunal flap. We used this technique in 11 patients. Four weeks after subtotal esophagectomy, reconstruction using free jejunal flaps was performed. A free jejunum was placed at the pre-sternum, and the internal thoracic artery and vein were usually used as the recipient vessels. There were no cases of flap necrosis and no hospital deaths. Anastomotic leakage occurred in two cases. Both leakages were cured by conservative treatment. Delayed esophageal reconstruction using a free jejunal flap can be considered to be a safe procedure when the stomach is unavailable as an esophageal substitute.
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Bortezomib reduces the tumorigenicity of multiple myeloma via downregulation of upregulated targets in clonogenic side population cells.
PLoS ONE
PUBLISHED: 01-16-2013
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Side population (SP) cells in cancers, including multiple myeloma, exhibit tumor-initiating characteristics. In the present study, we isolated SP cells from human myeloma cell lines and primary tumors to detect potential therapeutic targets specifically expressed in SP cells. We found that SP cells from myeloma cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11) express CD138 and that non-SP cells include a CD138-negative population. Serial transplantation of SP and non-SP cells into NOD/Shi-scid IL-2?nul mice revealed that clonogenic myeloma SP cells are highly tumorigenic and possess a capacity for self-renewal. Gene expression analysis showed that SP cells from five MM cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11, JJN3) express genes involved in the cell cycle and mitosis (e.g., CCNB1, CDC25C, CDC2, BIRC5, CENPE, SKA1, AURKB, KIFs, TOP2A, ASPM), polycomb (e.g., EZH2, EPC1) and ubiquitin-proteasome (e.g., UBE2D3, UBE3C, PSMA5) more strongly than do non-SP cells. Moreover, CCNB1, AURKB, EZH2 and PSMA5 were also upregulated in the SPs from eight primary myeloma samples. On that basis, we used an aurora kinase inhibitor (VX-680) and a proteasome inhibitor (bortezomib) with RPMI 8226 and AMO1 cells to determine whether these agents could be used to selectively target the myeloma SP. We found that both these drugs reduced the SP fraction, though bortezomib did so more effectively than VX-680 due to its ability to reduce levels of both phospho-histone H3 (p-hist. H3) and EZH2; VX-680 reduced only p-hist. H3. This is the first report to show that certain oncogenes are specifically expressed in the myeloma SP, and that bortezomib effectively downregulates expression of their products. Our approach may be useful for screening new agents with which to target a cell population possessing strong tumor initiating potential in multiple myeloma.
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Detection of breast cancer with a computer-aided detection applied to full-field digital mammography.
J Digit Imaging
PUBLISHED: 01-16-2013
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A study was conducted to evaluate the sensitivity of computer-aided detection (CAD) with full-field digital mammography in detection of breast cancer, based on mammographic appearance and histopathology. Retrospectively, CAD sensitivity was assessed in total group of 152 cases for subgroups based on breast density, mammographic presentation, lesion size, and results of histopathological examination. The overall sensitivity of CAD was 91 % (139 of 152 cases). CAD detected 100 % (47/47) of cancers manifested as microcalcifications; 98 % (62/63) of those manifested as non-calcified masses; 100 % (15/15) of those manifested as mixed masses and microcalcifications; 75 % (12/16) of those manifested as architectural distortions, and 69 % (18/26) of those manifested as focal asymmetry. CAD sensitivity was 83 % (10/12) for cancers measuring 1-10 mm, 92 % (37/40) for those measuring 11-20 mm, and 92 % (92/100) for those measuring >20 mm. There was no significant difference in CAD detection efficiency between cancers in dense breasts (88 %; 69/78) and those in non-dense breasts (95 %; 70/74). CAD showed a high sensitivity of 91 % (139/152) for the mammographic appearance of cancer and 100 % sensitivity for identifying cancers manifested as microcalcifications. Sensitivity was not influenced by breast density or lesion size. CAD should be effective for helping radiologists detect breast cancer at an earlier stage.
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FOXC2 Mutations in Familial and Sporadic Spinal Extradural Arachnoid Cyst.
PLoS ONE
PUBLISHED: 01-01-2013
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Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater. Most cases are sporadic; however, three familial SEDAC cases have been reported, suggesting genetic etiological factors. All familial cases are associated with lymphedema-distichiasis syndrome (LDS), whose causal gene is FOXC2. However, FOXC2 mutation analysis has been performed in only 1 family, and no mutation analysis has been performed on sporadic (non-familial) SEDACs. We recruited 17 SEDAC subjects consisting of 2 familial and 7 sporadic cases and examined FOXC2 mutations by Sanger sequencing and structural abnormalities by TaqMan copy number assay. We identified 2 novel FOXC2 mutations in 2 familial cases. Incomplete LDS penetrance was noted in both families. Four subjects presented with SEDACs only. Thus, SEDAC caused by the heterozygous FOXC2 loss-of-function mutation should be considered a feature of LDS, although it often manifests as the sole symptom. Seven sporadic SEDAC subjects had no FOXC2 mutations, no symptoms of LDS, and showed differing clinical characteristics from those who had FOXC2 mutations, suggesting that other gene(s) besides FOXC2 are likely to be involved in SEDAC.
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Anorectal transplantation in human cadavers: mock anorectal allotransplantation.
PLoS ONE
PUBLISHED: 01-01-2013
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Anorectal transplantation is a method for patients who have lost their anorectal function or suffer from congenital anorectal dysfunction to recover this function, and this has been investigated in experimental animal models using pigs, dogs, and rats. In this study, we performed an examination of anorectal transplantation in human cadavers to investigate whether this procedure could be performed in patients.
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Unilateral delayed eruption of a mandibular permanent canine and the maxillary first and second molars, and agenesis of the maxillary third molar.
Am J Orthod Dentofacial Orthop
PUBLISHED: 01-01-2013
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Delayed tooth eruption can affect the accuracy of orthodontic diagnosis and treatment planning and could delay overall treatment. A girl, aged 7 years 4 months, who had unilateral delayed eruption of several teeth was successfully treated. The evaluation of delayed tooth eruption should be considered by the orthodontist because the role of these teeth can affect the overall treatment of malocclusion. In patients with delayed tooth eruption, careful and accurate diagnosis and treatment planning will allow the orthodontist to start treatment at the proper stage and might reduce the overall orthodontic treatment time.
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CD48 as a novel molecular target for antibody therapy in multiple myeloma.
Br. J. Haematol.
PUBLISHED: 11-21-2011
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Monoclonal antibody (mAb) drugs are desirable for the improvement of multiple myeloma (MM) treatment. In this study, we found for the first time that CD48 was highly expressed on MM plasma cells. In 22 out of 24 MM patients, CD48 was expressed on more than 90% of MM plasma cells at significantly higher levels than it was on normal lymphocytes and monocytes. CD48 was only weakly expressed on some CD34(+) haematopoietic stem/progenitor cells, and not expressed on erythrocytes or platelets. We next examined whether CD48 could serve as a target antigen for mAb therapy against MM. A newly generated in-house anti-CD48 mAb induced mild antibody-dependent cell-mediated cytotoxicity and marked complement-dependent cytotoxicity against not only MM cell lines but also primary MM plasma cells in vitro. Administration of the anti-CD48 mAb significantly inhibited tumour growth in severe combined immunodeficient mice inoculated subcutaneously with MM cells. Furthermore, anti-CD48 mAb treatment inhibited growth of MM cells transplanted directly into murine bone marrow. Finally and importantly, we demonstrated that the anti-CD48 mAb did not damage normal CD34(+) haematopoietic stem/progenitor cells. These results suggest that the anti-CD48 mAb has the potential to become an effective therapeutic mAb against MM.
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FDG-PET/CT in the diagnosis of recurrent breast cancer.
Acta Radiol
PUBLISHED: 11-08-2011
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An advantage of PET/CT has been demonstrated for diagnosis of several tumor entities. In patients with breast cancer, early diagnosis and accurate restaging of recurrence after surgery is important for selection of the most appropriate therapeutic strategy. Purpose To evaluate the accuracy of integrated positron emission tomography and computed tomography (PET/CT) using 18F-fluorodeoxyglucose (FDG), for follow-up of patients with suspected recurrent breast cancer.
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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.