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In JoVE (1)

Other Publications (40)

Articles by James E. East in JoVE

 JoVE Immunology and Infection

Artificial Antigen Presenting Cell (aAPC) Mediated Activation and Expansion of Natural Killer T Cells

1Department of Microbiology and Immunology, University of Maryland


JoVE 4333

Here we describe a method for activating and expanding human NKT cells from bulk T cell populations using artificial antigen presenting cells (aAPC). The use of CD1d-based aAPC provides a standardized method for generating high numbers of functional NKT cells.

Other articles by James E. East on PubMed

Giant Brunner's Gland Hamartoma

Comprehensive Mucosal Visualization at Optical Colonoscopy: Technique Remains the Key

Statin Therapy After Stroke or Transient Ischemic Attack

Position Changes Improve Visibility During Colonoscope Withdrawal: a Randomized, Blinded, Crossover Trial

Adequate distension is essential to maximize neoplasia detection during colonoscope withdrawal. Position changes may improve distension but are often not performed in routine practice.

Narrow Band Imaging Avoids Potential Chromoendoscopy Risks

A Pilot Study of Intrastricture Steroid Versus Placebo Injection After Balloon Dilatation of Crohn's Strictures

Restricturing after ileocolonic resection for Crohn's disease is common. Colonoscopic balloon dilatation is effective but repeated dilatations often are required. Intrastricture steroid injection after balloon dilatation has been reported to reduce the need for repeat dilatation in retrospective series, but no randomized data are available.

Magnification Pan-chromoendoscopy Remains the Mainstay for Colitis Dysplasia Detection and Differentiation

Surface Visualization at CT Colonography Simulated Colonoscopy: Effect of Varying Field of View and Retrograde View

Colonoscopy is the gold standard for diagnosis of mucosal disease, but has a recognized "miss rate" for polyps probably because some lesions lie in areas of the colonic surface that do not enter the field of view. Using CT colonography (CTC) simulation this pilot study aimed to determine how much colonic surface is visualized with a standard, modern optical colonoscope (field of view 140 degrees ) with or without the addition of a retrograde viewing auxiliary imaging device (RVAID; 135 degrees ) and of a wide-angle (170 degrees ) colonoscope.

Comparison of Magnified Pit Pattern Interpretation with Narrow Band Imaging Versus Chromoendoscopy for Diminutive Colonic Polyps: a Pilot Study

Chromoendoscopy can accurately differentiate neoplastic from nonneoplastic polyps in the colon. Narrow band imaging (NBI) has been described as "electronic chromoendoscopy," but it is unclear whether pit patterns seen with chromoendoscopy are identical to those with NBI.

Look, Remove, and Discard: Can Narrow-band Imaging Replace Histopathology for Small Colorectal Polyps? It is Time to Push the Button!

Investigating Rectal Bleeding

What Are the Benefits of the Variable-stiffness Colonoscope?

Sporadic and Syndromic Hyperplastic Polyps and Serrated Adenomas of the Colon: Classification, Molecular Genetics, Natural History, and Clinical Management

There is now strong evidence for an alternative pathway of colorectal carcinogenesis implicating hyperplastic polyps and serrated adenomas. This article briefly reviews the evidence for this serrated pathway, provides diagnostic criteria for clinically significant hyperplastic polyps and allied serrated polyps, and suggests how this information may be translated into safe, effective guidelines for colonoscopy-based colon cancer prevention. Consideration also is given to the definition and management of hyperplastic polyposis syndrome. The currently proposed management plan for serrated polyps is tentative because of incomplete knowledge of the nature and behavior of these polyps. This article highlights key areas warranting further research.

Uni- and Bidirectional Wide Angle CT Colonography: Effect on Missed Areas, Surface Visualization, Viewing Time and Polyp Conspicuity

The effect of field of view on mucosal visualisation and reader efficiency during three-dimensional endoluminal CT colonography (CTC) was investigated. Twenty CTC datasets were reviewed at standard 90-degree and "wide" 140-degree viewing angles using customised viewing software (V3D colon; Viatronix), which listed number and size of missed mucosal areas ("missed regions tool") and percentage mucosal visualisation. We compared: (1) unidirectional and bidirectional flythrough using 140- versus 90-degree viewing angles; (2) reader analysis time comparing unidirectional 140-degree flythrough versus bidirectional 90-degree flythrough; (3) paired image snapshots of 12 polyps taken at each field of view were reviewed to assess conspicuity. All patients underwent conventional colonoscopy. Bidirectional 140-degree review reduced the numbers of missed areas by between eight- and 40-fold depending on size category, including those >1,000 mm(2), compared with standard 90-degree bidirectional flythrough (P < 0.001). Combined prone-supine unidirectional 140-degree flythrough and missed area review was 3.8 min faster than 90-degree bidirectional review (9.3 versus 5.5 min, P < 0.0001) for the same surface visualisation. When viewed as pairs, polyps were rated more conspicuous with a 90-degree field of view, P = 0.03. Wide-angle (140-degree) CTC can reduce both numbers of missed areas and review times. However, this may be at the expense of polyp conspicuity.

Novel Approaches in Colorectal Endoscopy: What Do We Need Biopsies For?

Magnification chromoendoscopy, narrow band imaging (NBI) and confocal endomicroscopy can all provide accurate assessment of small and diminutive colonic lesions for neoplastic change that approaches the accuracy of standard histopathology. It is likely that there will be a move to use these techniques in clinical practice for small and particularly diminutive, non-depressed lesions in the near future. Non-neoplastic lesions would be left in situ, and neoplastic lesions resected and disposed of without histopathological assessment. Histopathology would be reserved for larger lesions, indeterminate lesions or lesions where invasion was suspected. There are potentially significant cost savings and patient benefits, with a focussing of histopathological expertise on higher risk lesions, particularly in the era of bowel cancer screening. These techniques may also help target biopsies in colitis surveillance, removing the need for large numbers of random samples. However, in order to convince patients, histopathologists and those funding healthcare of the validity of this approach, further trial data will be needed, with an accreditation process for endoscopists wishing to take on this responsibility.

CT Colonography and Cost-effectiveness

CT colonography (CTC) is increasingly advocated as an effective initial screening tool for colorectal cancer. Nowadays, policy-makers are increasingly interested in cost-effectiveness issues. A number of studies assessing the cost-effectiveness of CTC have been published to date. The majority of findings indicate that CTC is probably not cost-effective when colonoscopy is available, but this conclusion is sensitive to a number of key parameters. This review discusses the findings of these studies, and considers those factors which most influence final conclusions, notably intervention costs, compliance rates, effectiveness of colonoscopy, and the assumed prevalence and natural history of diminutive advanced polyps.

Narrow Band Imaging at Colonoscopy: Seeing Through a Glass Darkly or the Light of a New Dawn?

Optical Diagnosis of Small Colorectal Polyps at Routine Colonoscopy (Detect InSpect ChAracterise Resect and Discard; DISCARD Trial): a Prospective Cohort Study

Accurate optical diagnosis of small (<10 mm) colorectal polyps in vivo, without formal histopathology, could make colonoscopy more efficient and cost effective. The aim of this study was to assess whether optical diagnosis of small polyps is feasible and safe in routine clinical practice.

Development of a Novel Esophageal Stricture Simulation

Esophageal stricture dilatation has a significant morbidity and mortality and training can be difficult to obtain. The aim of the study was to investigate the face validity of a novel stricture simulation and evaluate its utility for training in balloon-dilatation technique.

Management of Varices in Cirrhosis

Early Covered-stent Fracture After Placement for a Benign Esophageal Stricture

Commentary: Surveillance Colonoscopy: the Long and the Short of It

Synthesis and Structure-activity Relationships of Tyrosine-based Inhibitors of Autotaxin (ATX)

Autotaxin (ATX) is a secreted soluble enzyme that generates lysophosphatidic acid (LPA) through its lysophospholipase D activity. Because of LPA's role in neoplastic diseases, ATX is an attractive therapeutic target due to its involvement in LPA biosynthesis. Here we describe the SAR of ATX inhibitor, VPC8a202, and apply this SAR knowledge towards developing a high potency inhibitor. We found that electron density in the pyridine region greatly influences activity of our inhibitors at ATX.

Dynamic Patient Position Changes During Colonoscope Withdrawal Increase Adenoma Detection: a Randomized, Crossover Trial

Colonoscopy has a miss rate for adenomas that may partly relate to poor visualization of the colonic surface. Dynamic position changes during colonoscope withdrawal can improve luminal distension.

New 2010 British Society of Gastroenterology Colitis Surveillance Guidelines: Costs and Surveillance Intervals

Development and Validation of a Training Module on the Use of Narrow-band Imaging in Differentiation of Small Adenomas from Hyperplastic Colorectal Polyps

Experts are accurate in differentiating small adenomas from hyperplastic polyps at colonoscopy by using narrow-band imaging (NBI).

Development of Amidine-based Sphingosine Kinase 1 Nanomolar Inhibitors and Reduction of Sphingosine 1-phosphate in Human Leukemia Cells

Sphingosine 1-phosphate (S1P) is a bioactive lipid that has been identified as an accelerant of cancer progression. The sphingosine kinases (SphKs) are the sole producers of S1P, and thus, SphK inhibitors may prove effective in cancer mitigation and chemosensitization. Of the two SphKs, SphK1 overexpression has been observed in a myriad of cancer cell lines and tissues and has been recognized as the presumptive target over that of the poorly characterized SphK2. Herein, we present the design and synthesis of amidine-based nanomolar SphK1 subtype-selective inhibitors. A homology model of SphK1, trained with this library of amidine inhibitors, was then used to predict the activity of additional, more potent, inhibitors. Lastly, select amidine inhibitors were validated in human leukemia U937 cells, where they significantly reduced endogenous S1P levels at nanomolar concentrations.

Proceedings of a Preliminary Workshop at Gastro 2009--narrow Banding Imaging in Digestive Endoscopy: Clinical Outcome of Classification (Omed-Jges Educational Meeting Held on 22 November, 2009)

This publication reports the proceedings of the preliminary meeting of the working party that met at Gastro 2009 during the World Congress in London. The purpose of the preliminary meeting was to consider the areas that require attention, to discuss some of the findings that have already been published and to agree on the way forward. Our reason for publishing these proceedings is to stimulate interest in this venture and to provide the opportunity for input from the endoscopy community worldwide. The next meeting of the working party will be at the JGES Society meeting in Aomori in April 2011 when we hope to prepare a preliminary classification. This will be presented for general discussion and debate at the International Congress of Endoscopy (ICE) in Los Angeles in September 2011.

Development of a Phosphatase-resistant, L-tyrosine Derived LPA1/LPA3 Dual Antagonist

Lysophosphatidic acid (LPA) is a bioactive compound that has gained attention due to its role in neoplastic diseases. Our group has developed a potent dual LPA1/LPA3 receptor antagonist, VPC51098 (LPA1 IC(50) = 84 nM, LPA1 IC(50) = 48 nM) that contained a labile phosphate head group. This lability has impaired our evaluation of our scaffold of LPA receptor antagonists in vivo. We wished to replace the phosphate with a potentially more stable head group while retaining potency at both LPA1 and LPA3 to facilitate future in vivo studies. We tested in vitro potency of all head groups including α-methylene, α-fluoromethylene, α-hydroxymethylene; vinyl phosphonates; α-fluoro vinyl phosphonates. The most potent compound was found to be a low micromolar inhibitor VPC51299 that contained a vinyl phosphonate and possessed a half-life of approximately 90 min in rats when dosed intravenously. Herein, we describe the synthesis and initial biological evaluation of these compounds.

Improving the Quality of Colonoscopy

Proximal Serrated Polyp Detection at Colonoscopy: the Best of Times ...the Worst of Times?

Endoscopic Submucosal Dissection for Gastric Neoplasm in Patients with Co-morbidities Categorized According to the ASA Physical Status Classification

BACKGROUND: Endoscopic submucosal dissection (ESD) has come to be widely performed for reduced invasiveness; however, its safety in patients with co-morbidities is not fully examined. We aimed to evaluate the safety and efficacy of gastric ESD with co-morbidities categorized according to ASA Physical Status Classification. METHODS: Two hundred and forty patients of ASA 1 (no co-morbidities), 268 of ASA 2 (mild), and 19 of ASA 3 (severe) were treated by ESD for gastric neoplasms. We retrospectively compared clinicopathological features and treatment results of these three groups. RESULTS: Cases (by percent) treated with anticoagulant/platelet agents were more common in the higher ASA grades (ASA 1, 5.8%; ASA 2, 29.1%; ASA 3, 31.6%; P < 0.0001). There were no significant differences in case numbers treated under guideline criteria, curative resection (ASA 1, 79.6%; ASA 2, 79.9%; ASA 3, 78.9%), or complications related to the ESD procedure (e.g., postoperative bleeding, perforation, thermal injury). By a patient risk prediction model on surgery, i.e., P-POSSUM, morbidity was halved, and no patients died compared to a predicted death rate of 0.5-2%; however, total and complications unrelated to ESD procedure (e.g., aspiration pneumonia, ischemic heat attack) were more common in higher ASA grades (ASA 1, ASA 2, ASA 3: 15.4, 23.9, 26.3%, respectively, P = 0.014; 0.4, 7.1, 0%, respectively, P = 0.00087). Deviation rates from clinical pathway were more frequent and hospital stay (days) longer in higher ASA grades (ASA 1, ASA 2, ASA 3: 11.3, 17.9, 26.3%, respectively, P = 0.014; 8, 8, 9%, respectively, P = 0.0053). CONCLUSIONS: ESD is an efficient treatment for gastric neoplasms with co-morbidities. However, additional caution is required because co-morbidity is a risk factor for both total complications and complications unrelated to the ESD procedure, and may cause deviations in the clinical course and prolonged hospital stay.

Narrow Band Imaging for Detection of Dysplasia in Colitis: a Randomized Controlled Trial

In ulcerative colitis surveillance, chromoendoscopy improves dysplasia detection 3 – 5-fold compared with white light endoscopy (WLE). The aim of this study was to investigate whether narrow band imaging (NBI) can improve dysplasia detection compared with WLE.

High Prevalence of Hyperplastic Polyposis Syndrome (serrated Polyposis) in the NHS Bowel Cancer Screening Programme

Colonoscopic Cancer Surveillance in Inflammatory Bowel Disease: What's New Beyond Random Biopsy?

Colonoscopy based colitis surveillance is widely accepted to try to prevent development of and ensure early detection of colitis-associated colorectal cancer. Traditionally this has been performed with quadrantic random biopsies throughout the colon. Chromoendoscopy "dye-spray" with targeted biopsies only has been shown to increase dysplasia detection 4 to 5 fold on a per lesion basis. It has therefore been suggested that random biopsies should be abandoned as they do not increase dysplasia detection nor change patient clinical course. Recent British guidelines for colitis surveillance have strongly endorsed chromoendoscopy. This short review summarizes current international guidelines and looks at how to optimize white light colonoscopy in colitis considering: bowel preparation, withdrawal time, high definition, and structure enhancement. Data for advanced imaging techniques are reviewed including positive evidence in favor of chromoendoscopy, and limited data suggesting autofluoresence imaging may be promising. Narrow band imaging does not increase dysplasia detection in colitis. Confocal endomicroscopy might potentially reduce biopsies beyond that of chromoendoscopy but does not offer a clear detection advantage. Pan-colonic chromoendoscopy with targeted biopsies increases dysplasia detection and is the standard of care in the United Kingdom. It is likely that the use of chromoendoscopy for colitis surveillance will become widely accepted internationally.

Connecting the Dots: Artificial Antigen Presenting Cell-mediated Modulation of Natural Killer T Cells

Natural killer T (NKT) cells constitute an important subset of T cells that can both directly and indirectly mediate antitumor immunity. However, we and others have reported that cancer patients have a reduction in both NKT cell number and function. NKT cells can be stimulated and expanded with α-GalCer and cytokines and these expanded NKT cells retain their phenotype, remain responsive to antigenic stimulation, and display cytotoxic function against tumor cell lines. These data strongly favor the use of ex vivo expanded NKT cells in adoptive immunotherapy. NKT cell based-immunotherapy has been limited by the use of autologous antigen-presenting cells, which can vary substantially in their quantity and quality. A standardized system that relies on artificial antigen-presenting cells (aAPCs) could produce the stimulating effects of dendritic cell (DC) without the pitfalls of allo- or xenogeneic cells. In this review, we discuss the progress that has been made using CD1d-based aAPC and how this acellular antigen presenting system can be used in the future to enhance our understanding of NKT cell biology and to develop NKT cell-specific adoptive immunotherapeutic strategies.

1,635 Endoscopic Submucosal Dissection Cases in the Esophagus, Stomach, and Colorectum: Complication Rates and Long-term Outcomes

BACKGROUND: Endoscopic submucosal dissection (ESD) enables en bloc resection of early gastrointestinal neoplasms; however, most ESD articles report small series, with short-term outcomes performed by multiple operators on single organ. We assessed short- and long-term treatment outcomes following ESD for early neoplasms throughout the gastrointestinal tract. METHODS: We performed a longitudinal cohort study in single tertiary care referral center. A total of 1,635 early gastrointestinal neoplasms (stomach 1,136; esophagus 138; colorectum 361) were treated by ESD by single operator. Outcomes were complication rates, en bloc R0 resection rates, and long-term overall and disease-specific survival rates at 3 and 5 years for both guideline and expanded criteria for ESD. RESULTS: En bloc R0 resection rates were: stomach: 97.1 %; esophagus: 95.7 %; colorectum: 98.3 %. Postoperative bleeding and perforation rates respectively were: stomach: 3.6 and 1.8 %; esophagus: 0 and 0 %; colorectum: 1.7 and 1.9 %. Intra criteria resection rates were: stomach: 84.9 %; esophagus: 81.2 %; colorectum: 88.6 %. Three-year survival rates for lesions meeting Japanese ESD guideline/expanded criteria were for all organ-combined: 93.4/92.7 %. Five-year rates were: stomach: 88.1/84.6 %; esophagus: 81.6/57.3 %; colorectum: 94.3/100 %. Median follow-up period was 53.4 (range, 0.07-98.6) months. Follow-up rate was 94 % (1,020/1,085). There was no recurrence or disease-related death. CONCLUSIONS: In this large series by single operator, ESD was associated with high curative resection rates and low complication rates across the gastrointestinal tract. Disease-specific and overall long-term prognosis for patients with lesions within intra criteria after curative resection appeared to be excellent.

Raising the Roof: The Preferential Pharmacological Stimulation of Th1 and Th2 Responses Mediated by NKT Cells

Natural killer T (NKT) cells serve as a bridge between the innate and adaptive immune systems, and manipulating their effector functions can have therapeutic significances in the treatment of autoimmunity, transplant biology, infectious disease, and cancer. NKT cells are a subset of T cells that express cell-surface markers characteristic of both natural killer cells and T cells. These unique immunologic cells have been demonstrated to serve as a link between the innate and adaptive immune systems through their potent cytokine production following the recognition of a range of lipid antigens, mediated through presentation of the major histocompatibility complex (MHC) class I like CD1d molecule, in addition to the NKT cell's cytotoxic capabilities upon activation. Although a number of glycolipid antigens have been shown to complex with CD1d molecules, most notably the marine sponge derived glycolipid alpha-galactosylceramide (α-GalCer), there has been debate as to the identity of the endogenous activating lipid presented to the T-cell receptor (TCR) via the CD1d molecule on antigen-presenting cells (APCs). This review aims to survey the use of pharmacological agents and subsequent structure-activity relationships (SAR) that have given insight into the binding interaction of glycolipids with both the CD1d molecules as well as the TCR and the subsequent immunologic response of NKT cells. These studies not only elucidate basic binding interactions but also pave the way for future pharmacological modulation of NKT cell responses.

Principles of Quality Controlled Endoscopic Submucosal Dissection with Appropriate Dissection Level and High Quality Resected Specimen

Endoscopic submucosal dissection (ESD) has enabled en bloc resection of early stage gastrointestinal tumors with negligible risk of lymph node metastasis, regardless of tumor size, location, and shape. However, ESD is a relatively difficult technique compared with conventional endoscopic mucosal resection, requiring a longer procedure time and potentially causing more complications. For safe and reproducible procedure of ESD, the appropriate dissection of the ramified vascular network in the level of middle submucosal layer is required to reach the avascular stratum just above the muscle layer. The horizontal approach to maintain the appropriate depth for dissection beneath the vascular network enables treatment of difficult cases with large vessels and severe fibrosis. The most important aspect of ESD is the precise evaluation of curability. This approach can also secure the quality of the resected specimen with enough depth of the submucosal layer.

Cost-effective and Large-scale Synthesis of 16:0 Lysophosphatidic Acid

Lysophosphatidic acid (LPA) is a bioactive compound that has gained attention due to its role in neoplastic diseases. Popularity of the compound has necessitated the use of large quantities of the phospholipid for in vivo and in vitro testing but methods for generating LPA require the use costly procedures, namely phosphoramidite coupling reagents. Additionally there has been no reported large-scale synthesis of LPA. In the present study we report the cost-effective and large-scale synthesis of 16:0 LPA.

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