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Find video protocols related to scientific articles indexed in Pubmed.
Arthroscopic tenodesis of the long head of the biceps.
Orthopedics
PUBLISHED: 11-01-2014
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The long head of the biceps (LHB) is commonly implicated in shoulder pathology due to its anatomic course and intimacy with the rotator cuff and superior labrum of the glenoid. Treatment of tendinosis of the LHB may be required secondary to partial thickness tears, instability/subluxation, associated rotator cuff tears, or SLAP (superior labrum, anterior to posterior) lesions. Treatment options include open or arthroscopic techniques for tenodesis vs tenotomy. Controversy exists in the orthopedic literature regarding the preferred procedure. The all-arthroscopic biceps tenodesis technique is a viable and reproducible option for treatment. This article provides a review of the all-arthroscopic biceps tenodesis technique using proximal interference screw fixation and its subsequent postoperative regimen. All-arthroscopic biceps tenodesis maintains elbow flexion and supination power, minimizes cosmetic deformities, and leads to less fatigue soreness after active flexion. Thus, arthroscopic biceps tenodesis should be offered and encouraged as a treatment option for younger, active patients. [Orthopedics. 2014; 37(11):743-747.].
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Bilateral Diffusion-weighted MR Imaging of Breast Tumors with Submillimeter Resolution Using Readout-segmented Echo-planar Imaging at 7 T.
Radiology
PUBLISHED: 10-24-2014
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Purpose To evaluate the image quality, robustness, and diagnostic performance of submillimeter in-plane resolution diffusion-weighted ( DW diffusion-weighted ) magnetic resonance (MR) imaging at 7 T in the assessment of breast tumors. Materials and Methods Institutional review board approval and written informed consent of five volunteers and 33 patients with 33 breast lesions (31 with histopathologic confirmation, two with confirmation at follow-up) were obtained. Image quality optimization and comparisons of readout-segmented echo-planar imaging ( rs-EPI readout-segmented echo-planar imaging ) and single-shot echo-planar imaging ( ss-EPI single-shot echo-planar imaging ) with or without parallel imaging were performed in volunteers. In all patients, bilateral DW diffusion-weighted imaging was performed in 3 minutes 35 seconds by using combined rs-EPI readout-segmented echo-planar imaging and parallel imaging with 0.9 × 0.9 mm in-plane resolution with a 7-T whole-body MR imager. Image quality, lesion conspicuity, and image properties (ie, signal-to-noise ratio, contrast-to-noise ratio) were assessed. Regions of interest were drawn in the largest lesion in each patient (23 malignant lesions, 10 benign lesions) by two independent readers. Apparent diffusion coefficient ( ADC apparent diffusion coefficient ) values were used to differentiate between benign and malignant breast tumors. Results DW diffusion-weighted imaging with combined parallel imaging and rs-EPI readout-segmented echo-planar imaging reduced artifacts (ie, blurring and geometric distortions) by a calculated factor of seven when compared with DW diffusion-weighted imaging with ss-EPI single-shot echo-planar imaging , and it improved image quality from a score of 1 of 10 to a score of 8 of 10. The rs-EPI readout-segmented echo-planar imaging sequence with a b value of 0 sec/mm(2) yielded high-spatial-resolution T2-weighted MR images. An ADC apparent diffusion coefficient threshold of 1.275 × 10(-3) mm(2)/sec enabled differentiation between benign and malignant breast lesions, with sensitivity and specificity of 96% and 100%, respectively, for both independent readers. Conclusion At 7 T, one DW diffusion-weighted imaging examination of less than 4 minutes yielded high-quality ADC apparent diffusion coefficient maps and high-spatial-resolution T2-weighted MR images that were used to assess tumor and breast morphology. ADC apparent diffusion coefficient quantification alone enabled excellent differentiation of benign and malignant breast lesions. © RSNA, 2014 Online supplemental material is available for this article.
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Chimeric antigen receptor T cells for sustained remissions in leukemia.
N. Engl. J. Med.
PUBLISHED: 10-16-2014
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Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.
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Long-term Survival and Late Effects among 1-year Survivors of Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Acute Leukemia and Myelodysplastic Syndromes.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-19-2014
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We analyzed the outcomes of patients who survived disease-free for 1-year or more following second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant following disease relapse; among these 325 survived relapse-free at 1-year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplant in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least one year were 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status prior to second HCT was significantly associated with higher risk for overall mortality (HR 1.71 for patients with disease not in complete remission prior to second HCT, P<0.01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults following second transplant. Chronic GVHD was the leading cause of non-relapse mortality followed by organ failure and infection. The cumulative incidence of developing at least one of the studied late effects at 10-years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence 22%) and cataracts (20%), and in adults were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease-free for at least 1-year, many can be expected to survive long term. However, they continue to be at risk for relapse and non-relapse morbidity and mortality. Novel approaches are needed to minimize relapse risk and long-term transplant morbidity in this population.
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The clinical utility of reduced-distortion readout-segmented echo-planar imaging in the head and neck region: initial experience.
Eur Radiol
PUBLISHED: 08-13-2014
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To evaluate whether readout-segmented echo-planar imaging (RS-EPI) diffusion weighted image (DWI) can diminish image distortion in the head and neck area, compared with single-shot (SS)-EPI DWI.
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Optimal management of ankle syndesmosis injuries.
Open Access J Sports Med
PUBLISHED: 08-05-2014
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Syndesmosis injuries occur when there is a disruption of the distal attachment of the tibia and fibula. These injuries occur commonly (up to 18% of ankle sprains), and the incidence increases in the setting of athletic activity. Recognition of these injuries is key to preventing long-term morbidity. Diagnosis and treatment of these injuries requires a thorough understanding of the normal anatomy and the role it plays in the stability of the ankle. A complete history and physical examination is of paramount importance. Patients usually experience an external rotation mechanism of injury. Key physical exam features include detailed documentation about areas of focal tenderness (syndesmosis and deltoid) and provocative maneuvers such as the external rotation stress test. Imaging workup in all cases should consist of radiographs with the physiologic stress of weight bearing. If these images are inconclusive, then further imaging with external rotation stress testing or magnetic resonance imaging are warranted. Nonoperative treatment is appropriate for stable injuries. Unstable injuries should be treated operatively. This consists of stabilizing the syndesmosis with either trans-syndesmotic screw or tightrope fixation. In the setting of a concomitant Weber B or C fracture, the fibula is anatomically reduced and stabilized with a standard plate and screw construct. Proximal fibular fractures, as seen in the Maisonneuve fracture pattern, are not repaired operatively. Recent interest is moving toward repair of the deltoid ligament, which may provide increased stability, especially in rehabilitation protocols that involve early weight bearing. Rehabilitation is focused on allowing patients to return to their pre-injury activities as quickly and safely as possible. Protocols initially focus on controlling swelling and recovery from surgery. The protocols then progress to restoration of motion, early protected weight bearing, restoration of strength, and eventually a functional progression back to desired activities.
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R-CHOP or R-HyperCVAD With or Without Autologous Stem Cell Transplantation for Older Patients With Mantle Cell Lymphoma.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 08-01-2014
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Although intensive induction and autologous stem cell transplantation (ASCT) prolong survival in younger patients with mantle cell lymphoma (MCL), benefit in older patients remains uncertain because data supporting these approaches come almost exclusively from younger cohorts.
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Understanding the variability of properties in Antheraea pernyi silk fibres.
Soft Matter
PUBLISHED: 07-18-2014
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Variability is a common feature of natural silk fibres, caused by a range of natural processing conditions. Better understanding of variability will not only be favourable for explaining the enviable mechanical properties of animal silks but will provide valuable information for the design of advanced artificial and biomimetic silk-like materials. In this work, we have investigated the origin of variability in forcibly reeled Antheraea pernyi silks from different individuals using dynamic mechanical thermal analysis (DMTA) combined with the effect of polar solvent penetration. Quasi-static tensile curves in different media have been tested to show the considerable variability of tensile properties between samples from different silkworms. The DMTA profiles (as a function of temperature or humidity) through the glass transition region of different silks as well as dynamic mechanical properties after high temperature and water annealing are analysed in detail to identify the origin of silk variability in terms of molecular structures and interactions, which indicate that different hydrogen bonded structures exist in the amorphous regions and they are notably different for silks from different individuals. Solubility parameter effects of solvents are quantitatively correlated with the different glass transitions values. Furthermore, the overall ordered fraction is shown to be a key parameter to quantify the variability in the different silk fibres, which is consistent with DMTA and FTIR observations.
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Housing tubes from the marine worm Chaetopterus sp.: biomaterials with exceptionally broad thermomechanical properties.
J R Soc Interface
PUBLISHED: 07-11-2014
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The housing tube material of the marine worm Chaetopterus sp. exhibits thermal stability up to 250°C, similar to other biological materials such as mulberry silkworm cocoons. Interestingly, however, dynamic mechanical thermal analysis conducted in both air and water elucidated the lack of a glass transition in the organic tube wall material. In fact, the viscoelastic properties of the anhydrous and undried tube were remarkably stable (i.e. constant and reversible) between -75°C and 200°C in air, and 5°C and 75°C in water, respectively. Moreover, it was found that hydration and associated-water plasticization were key to the rubber-like flexible properties of the tube; dehydration transformed the material behaviour to glass-like. The tube is made of bionanocomposite fibrils in highly oriented arrangement, which we argue favours the biomaterial to be highly crystalline or cross-linked, with extensive hydrogen and/or covalent bonds. Mechanical property characterization in the longitudinal and transverse directions ascertained that the tubes were not quasi-isotropic structures. In general, the higher stiffness and strength in the transverse direction implied that there were more nanofibrils orientated at ± 45° and ± 65° than at 0° to the tube axis. The order of the mechanical properties of the soft-tough tubes was similar to synthetic rubber-like elastomers and even some viscid silks. The complex structure-property relations observed indicated that the worm has evolved to produce a tubular housing structure which can (i) function stably over a broad range of temperatures, (ii) endure mechanical stresses from specific planes/axes, and (iii) facilitate rapid growth or repair.
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Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT.
Blood
PUBLISHED: 06-30-2014
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Grades 2-4 acute graft-versus-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary end point of the trial was to compare 114-day grades 2-4 acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There was no difference in the probability of day 114 grades 2-4 acute GVHD-free survival (67% vs 62%, P = .38). Grades 2-4 GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs 34%, P = .48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs 16 days, P < .001; 16 vs 19 days, P = .03). Oropharyngeal mucositis was less severe in the Tac/Sir arm (peak Oral Mucositis Assessment Scale score 0.70 vs 0.96, P < .001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival, and overall survival at 2 years were no different between study arms (53% vs 45%, P = .06; 53% vs 54%, P = .77; and 59% vs 63%, P = .36). Based on similar long-term outcomes, more rapid engraftment, and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. This study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; and the trial was registered at www.clinicaltrials.gov as #NCT00406393.
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Improved survival after transplantation of more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMTCTN 0201.
J. Clin. Oncol.
PUBLISHED: 06-30-2014
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To characterize relationships between specific immune cell subsets in bone marrow (BM) or granulocyte colony-stimulating factor-mobilized peripheral blood (PB) stem cells collected from unrelated donors and clinical outcomes of patients undergoing transplantation in BMTCTN 0201.
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Current concepts in the diagnosis and management of cytokine release syndrome.
Blood
PUBLISHED: 05-29-2014
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As immune-based therapies for cancer become potent, more effective, and more widely available, optimal management of their unique toxicities becomes increasingly important. Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon ?, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without corticosteroids, can reverse the syndrome. However, because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life-threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of CRS based on severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS.
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Novel treatments for chronic lymphocytic leukemia and moving forward.
Am Soc Clin Oncol Educ Book
PUBLISHED: 05-27-2014
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The last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These include the antibody obintutuzumab (GA-101), as well as small-molecule inhibitors of key pathways involved in the pathogenesis of CLL, specifically the B-cell receptor (BCR) pathway (especially Bruton's tyrosine kinase [BTK] and P13K), and the antiapoptotic pathway (especially BCL-2). We will consider each in turn, focusing on the molecules most advanced in clinical development. There has also been extensive development in rewiring the patient's own immune system to treat CLL. This has been done through modifying autologous T cells to express a chimeric antigen receptor (CAR). Thus far all CAR-T preparations have targeted the CD19 antigen. This is a good rational for B-cell malignancies as CD19 expression is limited to B-cell malignancies and normal B cells. The in vivo amplification of the transduced T cells relies on signaling and co-signaling domains and provides significant killing of CLL cells. As exciting as these novel agents and approaches are, they obviously beg the question, will chemotherapy as a treatment for CLL soon be obsolete? Although chemotherapy is associated with known short-term toxicities, it has the advantage of being completed in a short period of time and being relatively inexpensive in comparison to novel therapies. In addition, long-term follow-up of results with chemoimmunotherapy have now identified a group of patients whose remissions are maintained for more than 10 years. An important question that will arise going forward is how to incorporate novel agents without eliminating the long term benefits possible with chemoimmunotherapy in a subset of patients with CLL.
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Early donor chimerism levels predict relapse and survival after allogeneic stem cell transplantation with reduced-intensity conditioning.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-23-2014
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The success of hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) is limited by a high rate of disease relapse. Early risk assessment could potentially improve outcomes by identifying appropriate patients for preemptive strategies that may ameliorate this high risk. Using a series of landmark analyses, we investigated the predictive value of early (day-30) donor chimerism measurements on disease relapse, graft-versus-host disease, and survival in a cohort of 121 patients allografted with a uniform RIC regimen. Chimerism levels were analyzed as continuous variables. In multivariate analysis, day-30 whole blood chimerism levels were significantly associated with relapse (hazard ratio [HR] = .90, P < .001), relapse-free survival (HR = .89, P < .001), and overall survival (HR = .94, P = .01). Day-30 T cell chimerism levels were also significantly associated with relapse (HR = .97, P = .002), relapse-free survival (HR = .97, P < .001), and overall survival (HR = .99, P = .05). Multivariate models that included T cell chimerism provided a better prediction for these outcomes compared with whole blood chimerism. Day-30 chimerism levels were not associated with acute or chronic graft-versus-host disease. We found that high donor chimerism levels were significantly associated with a low lymphocyte count in the recipient before transplant, highlighting the impact of pretransplant lymphopenia on the kinetics of engraftment after RIC HSCT. In summary, low donor chimerism levels are associated with relapse and mortality and can potentially be used as an early predictive and prognostic marker. These findings can be used to design novel approaches to prevent relapse and to improve survival after RIC HSCT.
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Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma.
Autophagy
PUBLISHED: 05-20-2014
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The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.
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Linking naturally and unnaturally spun silks through the forced reeling of Bombyx mori.
Acta Biomater
PUBLISHED: 05-12-2014
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The forced reeling of silkworms offers the potential to produce a spectrum of silk filaments, spun from natural silk dope and subjected to carefully controlled applied processing conditions. Here we demonstrate that the envelope of stress-strain properties for forced reeled silks can encompass both naturally spun cocoon silk and unnaturally processed artificial silk filaments. We use dynamic mechanical thermal analysis (DMTA) to quantify the structural properties of these silks. Using this well-established mechanical spectroscopic technique, we show high variation in the mechanical properties and the associated degree of disordered hydrogen-bonded structures in forced reeled silks. Furthermore, we show that this disorder can be manipulated by a range of processing conditions and even ameliorated under certain parameters, such as annealing under heat and mechanical load. We conclude that the powerful combination of forced reeling silk and DMTA has tied together native/natural and synthetic/unnatural extrusion spinning. The presented techniques therefore have the ability to define the potential of Bombyx-derived proteins for use in fibre-based applications and serve as a roadmap to improve fibre quality via post-processing.
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Engineered T cells for cancer therapy.
Cancer Immunol. Immunother.
PUBLISHED: 05-08-2014
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It is now well established that the immune system can control and eliminate cancer cells. Adoptive T cell transfer has the potential to overcome the significant limitations associated with vaccine-based strategies in patients who are often immune compromised. Application of the emerging discipline of synthetic biology to cancer, which combines elements of genetic engineering and molecular biology to create new biological structures with enhanced functionalities, is the subject of this focused research review.
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Differential Scanning Fluorimetry provides high throughput data on silk protein transitions.
Sci Rep
PUBLISHED: 04-22-2014
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Here we present a set of measurements using Differential Scanning Fluorimetry (DSF) as an inexpensive, high throughput screening method to investigate the folding of silk protein molecules as they abandon their first native melt conformation, dehydrate and denature into their final solid filament conformation. Our first data and analyses comparing silks from spiders, mulberry and wild silkworms as well as reconstituted 'silk' fibroin show that DSF can provide valuable insights into details of silk denaturation processes that might be active during spinning. We conclude that this technique and technology offers a powerful and novel tool to analyse silk protein transitions in detail by allowing many changes to the silk solutions to be tested rapidly with microliter scale sample sizes. Such transition mechanisms will lead to important generic insights into the folding patterns not only of silks but also of other fibrous protein (bio)polymers.
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The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists.
Bioorg. Med. Chem. Lett.
PUBLISHED: 03-13-2014
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A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrimidine 2-((2,6-dichlorobenzyl)thio)-5-isocyano-6-phenylpyrimidin-4-ol 4, resulting in the discovery of CXCR2 receptor antagonist 2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol 24. The SAR was investigated by systematic variation of the aromatic group at c-6, the linker between c-2 and the halogenated ring, and the c-5 nitrile moiety.
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Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells.
Blood
PUBLISHED: 03-04-2014
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Many patients with acute myeloid leukemia (AML) are incurable with chemotherapy and may benefit from novel approaches. One such approach involves the transfer of T cells engineered to express chimeric antigen receptors (CARs) for a specific cell-surface antigen. This strategy depends upon preferential expression of the target on tumor cells. To date, the lack of AML-specific surface markers has impeded development of such CAR-based approaches. CD123, the transmembrane ? chain of the interleukin-3 receptor, is expressed in the majority of AML cells but is also expressed in many normal hematopoietic cells. Here, we show that CD123 is a good target for AML-directed CAR therapy, because its expression increases over time in vivo even in initially CD123(dim) populations, and that human CD123-redirected T cells (CART123) eradicate primary AML in immunodeficient mice. CART123 also eradicated normal human myelopoiesis, a surprising finding because anti-CD123 antibody-based strategies have been reportedly well tolerated. Because AML is likely preceded by clonal evolution in "preleukemic" hematopoietic stem cells, our observations support CART123 as a viable AML therapy, suggest that CART123-based myeloablation may be used as a novel conditioning regimen for hematopoietic cell transplantation, and raise concerns for the use of CART123 without such a rescue strategy.
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A pre-steady state and steady state kinetic analysis of the N-ribosyl hydrolase activity of hCD157.
Arch. Biochem. Biophys.
PUBLISHED: 02-27-2014
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hCD157 catalyzes the hydrolysis of nicotinamide riboside (NR) and nicotinic acid riboside (NAR). The release of nicotinamide or nicotinic acid from NR or NAR was confirmed by spectrophotometric, HPLC and NMR analyses. hCD157 is inactivated by a mechanism-based inhibitor, 2'-deoxy-2'-fluoro-nicotinamide arabinoside (fNR). Modification of the enzyme during the catalytic cycle by NR, NAR, or fNR increased the intrinsic protein fluorescence by approximately 50%. Pre-steady state and steady state data were used to derive a minimal kinetic scheme for the hydrolysis of NR. After initial complex formation a reversible step (360 and 30s(-1)) is followed by a slow irreversible step (0.1s(-1)) that defined the rate limiting step, or kcat. The calculated KMapp value for NR in the hydrolytic reaction is 6nM. The values of the kinetic constants suggest that one biological function of cell-surface hCD157 is to bind and slowly hydrolyze NR, possibly converting it to a ligand-activated receptor. Differences in substrate preference between hCD157 and hCD38 were rationalized through a comparison of the crystal structures of the two proteins. This comparison identified several residues in hCD157 (F108 and F173) that can potentially hinder the binding of dinucleotide substrates (NAD(+)).
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Antibody-modified T cells: CARs take the front seat for hematologic malignancies.
Blood
PUBLISHED: 02-27-2014
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T cells redirected to specific antigen targets with engineered chimeric antigen receptors (CARs) are emerging as powerful therapies in hematologic malignancies. Various CAR designs, manufacturing processes, and study populations, among other variables, have been tested and reported in over 10 clinical trials. Here, we review and compare the results of the reported clinical trials and discuss the progress and key emerging factors that may play a role in effecting tumor responses. We also discuss the outlook for CAR T-cell therapies, including managing toxicities and expanding the availability of personalized cell therapy as a promising approach to all hematologic malignancies. Many questions remain in the field of CAR T cells directed to hematologic malignancies, but the encouraging response rates pave a wide road for future investigation.
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Screening for genes coding for putative antitumor compounds, antimicrobial and enzymatic activities from haloalkalitolerant and haloalkaliphilic bacteria strains of Algerian Sahara Soils.
Biomed Res Int
PUBLISHED: 02-26-2014
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Extreme environments may often contain unusual bacterial groups whose physiology is distinct from those of normal environments. To satisfy the need for new bioactive pharmaceuticals compounds and enzymes, we report here the isolation of novel bacteria from an extreme environment. Thirteen selected haloalkalitolerant and haloalkaliphilic bacteria were isolated from Algerian Sahara Desert soils. These isolates were screened for the presence of genes coding for putative antitumor compounds using PCR based methods. Enzymatic, antibacterial, and antifungal activities were determined by using cultural dependant methods. Several of these isolates are typical of desert and alkaline saline soils, but, in addition, we report for the first time the presence of a potential new member of the genus Nocardia with particular activity against the yeast Saccharomyces cerevisiae. In addition to their haloalkali character, the presence of genes coding for putative antitumor compounds, combined with the antimicrobial activity against a broad range of indicator strains and their enzymatic potential, makes them suitable for biotechnology applications.
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Comparison of the independent and combined effects of sub-chronic therapy with metformin and a stable GLP-1 receptor agonist on cognitive function, hippocampal synaptic plasticity and metabolic control in high-fat fed mice.
Neuropharmacology
PUBLISHED: 02-25-2014
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Cognitive dysfunction is more common in individuals with type 2 diabetes (T2DM). Currently, glucagon-like peptide-1 (GLP-1) and metformin are important therapeutic options for patients with T2DM. However, their potential effects on cognitive function, including underlying mechanisms, are yet to be fully determined. We have compared the individual and combined effects of treatment for 20 days with (Val(8))GLP-1(GluPAL), an enzymatically stable GLP-1-receptor agonist, and metformin on metabolic control and aspects of learning and memory in high fat fed mice. (Val(8))GLP-1(GluPAL) treatment for 20 days alone, or in combination with metformin, improved (p < 0.05) the recognition index in high fat mice, indicating enhanced learning and memory. In addition, these mice exhibited a complete reversal of the deleterious effects of prolonged high-fat feeding on long-term potentiation in the hippocampal CA1 region. This was linked to reduced hippocampal levels of 8-oxoguanine (p < 0.01) and glial fibriallary acidic protein (p < 0.001), indicating decreased oxidative stress and inflammation; respectively. Expression of fundamental hippocampal genes including mTOR, VEGF, NTRK2 and SIRT1 was also increased significantly (p < 0.001) by all treatments. (Val(8))GLP-1(GluPAL) monotherapy, or in combination with metformin, reduced circulating glucose (p < 0.05) and increased insulin (p < 0.05 to p < 0.01) concentrations, as well as improving glucose tolerance (p < 0.001) and glucose-stimulated insulin secretion (p < 0.05 to p < 0.01). Insulin sensitivity and measurements of energy regulation and metabolic rate were not altered. These studies highlight the neuroprotective properties of (Val(8))GLP-1(GluPAL), alone and in combination with metformin, in T2DM.
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Modern Trunnions Are More Flexible: A Mechanical Analysis of THA Taper Designs.
Clin. Orthop. Relat. Res.
PUBLISHED: 02-24-2014
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There is renewed concern surrounding the potential for corrosion at the modular head-neck junction to cause early failure in contemporary THAs. Although taper corrosion involves a complex interplay of many factors, a previous study suggested that a decrease in flexural rigidity of the femoral trunnion may be associated with an increased likelihood of corrosion at retrieval.
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Clinical features, management, and prognosis of an international series of 161 patients with limited-stage diffuse large B-cell lymphoma of the bone (the IELSG-14 study).
Oncologist
PUBLISHED: 02-24-2014
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The clinical features, management, and prognosis of stage I-II diffuse large B-cell lymphoma of the bone (PB-DLBCL) included in an international database of 499 lymphoma patients with skeletal involvement were reviewed.
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Diffusion tensor imaging analysis of optic radiation using readout-segmented echo-planar imaging.
Surg Radiol Anat
PUBLISHED: 02-10-2014
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To investigate the diffusion tensor imaging parameters of the optic radiation and surrounding structures using the high-resolution readout-segmented diffusion tensor imaging method.
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Scan time reduction for readout-segmented EPI using simultaneous multislice acceleration: Diffusion-weighted imaging at 3 and 7 Tesla.
Magn Reson Med
PUBLISHED: 02-04-2014
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Readout-segmented echo-planar imaging (rs-EPI) can provide high quality diffusion data because it is less prone to distortion and blurring artifacts than single-shot echo-planar imaging (ss-EPI), particularly at higher resolution and higher field. Readout segmentation allows shorter echo-spacing and echo train duration, resulting in reduced image distortion and blurring, respectively, in the phase-encoding direction. However, these benefits come at the expense of longer scan times because the segments are acquired in multiple repetitions times (TRs). This study shortened rs-EPI scan times by reducing the TR duration with simultaneous multislice acceleration.
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Prevalence of hyponatremia in acute medical admissions in tropical Asia Pacific Australia.
Asian Pac J Trop Med
PUBLISHED: 01-15-2014
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To determine prevalence of hyponatremia in acute medical admissions in Northern Australasia.
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Readout-segmented echo-planar imaging in diffusion-weighted mr imaging in breast cancer: comparison with single-shot echo-planar imaging in image quality.
Korean J Radiol
PUBLISHED: 01-10-2014
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The purpose of this study was to compare the image quality of standard single-shot echo-planar imaging (ss-EPI) and that of readout-segmented EPI (rs-EPI) in patients with breast cancer.
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Readout-segmented echo-planar imaging for diffusion-weighted imaging in the pelvis at 3T-A feasibility study.
Acad Radiol
PUBLISHED: 01-08-2014
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Diffusion-weighted imaging (DWI) of the pelvis at 3T is prone to artifacts that diminish the image quality. Readout-segmented echo-planar imaging (RS-EPI) is a new DWI technique that can reduce the artifacts associated with standard single-shot echo-planar imaging (SS-EPI) DWI. The purpose of this study was to evaluate the feasibility and image quality of RS-EPI in pelvic DWI compared to SS-EPI on a 3T imaging system.
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Clinical features, management and prognosis of multifocal primary bone lymphoma: a retrospective study of the international extranodal lymphoma study group (the IELSG 14 study).
Br. J. Haematol.
PUBLISHED: 01-02-2014
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'Multifocal bone lymphoma' or 'polyostotic lymphoma' is a neoplasm with exclusive multifocal involvement of the skeleton, without affecting lymph nodes or other soft tissues. Knowledge on this uncommon condition is limited because the related literature is sparse and fragmentary. We reviewed cases of multifocal bone diffuse large B-cell lymphoma (MB-DLBCL) registered in a clinico-pathological database of the International Extranodal Lymphoma Study Group that includes 499 cases of bone lymphoma. Clinical features, management and prognosis of 37 MB-DLBCL patients and 63 'controls' (stage-IV DLBCL and skeletal involvement) were analysed. Presentation and treatment of MB-DLBCL and controls were identical. At a median follow-up of 52 months (10-189), MB-DLBCL patients exhibited a significantly better response rate (92% vs. 65%; P = 0·002), progression-free survival (5-year: 56 ± 9% vs. 34 ± 6%; P = 0·003) and overall survival (5-year: 74 ± 8% vs. 36 ± 7%; P = 0·002). Among MB-DLBCL patients, the use of post-chemo radiotherapy was associated with better overall survival (5-year: 83 ± 12% vs. 55 ± 16%; P = 0·003). Two MB-DLBCL patients (5·4%) with spine and skull involvement experienced central nervous system (CNS) relapse. Thus, MB-DLBCL patients exhibit a significantly better prognosis compared to patients with advanced-stage DLBCL, and should be treated with conventional anthracycline-based chemotherapy, keeping intensified treatment for relapsing cases, considering involved-field radiotherapy, and CNS prophylaxis in high-risk patients.
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Acute Achilles Tendon Repair: Strength Outcomes After an Acute Bout of Exercise in Recreational Athletes.
Foot Ankle Int
PUBLISHED: 12-11-2013
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This is the first study to evaluate the effect of an acute bout of exercise on strength evaluation after Achilles tendon (AT) rupture and repair.
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CAR-modified anti-CD19 T cells for the treatment of B-cell malignancies: rules of the road.
Expert Opin Biol Ther
PUBLISHED: 11-21-2013
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Introduction: Malignancies of the B lymphocyte or its precursor include B-cell non-Hodgkin lymphoma as well as chronic and acute lymphoid leukemias. These are among the most common hematologic malignancies and many patients with B-cell malignancies are incurable. Although most patients initially respond to first-line treatment, relapse is frequent and is associated with a poor prognosis. T cells that are genetically engineered to express chimeric antigen receptors (CARs) recognizing the B-cell-associated molecule CD19 have emerged as a potentially potent and exciting therapeutic modality in recent years. Areas covered: This review explores the current peer-reviewed publications in the field and a discussion of expert opinion. Expert opinion: Genetic engineering of T cells has become clinically feasible and appears to be safe. Here we provide an insight into the process of patient selection, engineered T-cell production, infusion procedure, expected toxicities and efficacy of this exciting approach as it is practiced in the treatment of B-cell malignancies. Anti-CD19-redirected T cells likely represent the vanguard of an exciting new approach to treating cancer.
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Chimeric Antigen Receptor Therapy for Cancer.
Annu. Rev. Med.
PUBLISHED: 11-20-2013
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Improved outcomes for patients with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, synthetic biology, and cell-processing technologies has paved the way for clinical applications of chimeric antigen receptor-based therapies. This new form of targeted immunotherapy merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and on elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer. Expected final online publication date for the Annual Review of Medicine Volume 65 is January 14, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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Utility of a Fecal Real-time PCR Protocol for Detection of Mycobacterium bovis Infection in African Buffalo (Syncerus caffer).
J. Wildl. Dis.
PUBLISHED: 10-25-2013
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abstract : A real-time PCR protocol for detecting Mycobacterium bovis in feces was evaluated in bovine tuberculosis-infected African buffalo (Syncerus caffer). Fecal samples spiked with 1.42×10(3) cells of M. bovis culture/g and Bacille Calmette-Guérin standards with 1.58×10(1) genome copies/well were positive by real-time PCR but all field samples were negative.
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Do medical procedures in the arm increase the risk of lymphoedema after axillary surgery? A review.
ANZ J Surg
PUBLISHED: 10-20-2013
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Lymphoedema of the arm is a potentially serious consequence of any axillary procedure performed during the management of breast cancer. In an attempt to reduce its incidence and severity, patients are instructed to avoid venepunctures and blood pressure measurements on the treated arm. These precautions are not possible in some patients and attempts to adhere to them can cause discomfort, anxiety and stress for both patients and their health-care workers. The strength with which these recommendations are made is in contrast to the level of evidence underpinning them. This paper reviews this evidence regarding the safety, or lack thereof, of blood pressure monitoring and intravenous puncture in women who have had axillary surgery. With this evidence generally being anecdotal in nature, there appears to be no rigorous evidence-based support for the risk-reduction behaviours of avoiding blood pressure monitoring and venepuncture in the affected arm in the prevention of lymphoedema after axillary procedure. A clinical trial was proposed to investigate whether such avoidance measures were valuable, but failed during its inception. There remains a need for research from prospective trials on this controversial topic to determine the most appropriate patient recommendations that should be provided after axillary procedure regarding the risks for development of lymphoedema.
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Using solvents with different molecular sizes to investigate the structure of Antheraea pernyi silk.
Biomacromolecules
PUBLISHED: 10-07-2013
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The interaction between silk and polar solvents of different molecular size can be an important tool for understanding the structural features of natural silk; in particular, the disordered regions associated with the key property of mechanical toughness. In this work, we investigate the transitions induced in the tensile performance and structure of as-reeled Antheraea pernyi silks from different silkworms by a range of solvents that can only soften the protein chains in the amorphous regions. The results indicate that polar solvents with different molecular sizes affect the silk to different degrees, and silks with slightly different structures display significantly different tensile performance in the same solvent. The solvent molecular size is quantitatively correlated with the accessible volume in the amorphous regions before and after the yield point, which suggests that the volume accessible to the solvent molecules decreases as the solvent radius increases. Moreover, silks with more ordered structure (less free volume) in the amorphous regions are less sensitive to solvents than those with more disordered structures. However, silks with higher free volume have higher toughness due to the greater strain to failure.
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The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists.
Bioorg. Med. Chem. Lett.
PUBLISHED: 08-30-2013
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A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrazolopyrimidine 2-methyl-5-((phenylthio)methyl)pyrazolo[1,5-a]pyrimidin-7-ol 1, resulting in the discovery of CXCR2 receptor antagonist 2-benzyl-5-(((2,3-difluorophenyl)thio)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol 14. The SAR was investigated by systematic variation of the pendant thiol, alkyl and pyrimidinol groups. Replacement of the pyrazolopyrimidine core with a triazolo alternative led to a dual series of antagonists with favourable biological and pharmacokinetic properties.
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Proceedings from the National Cancer Institutes Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part III. Prevention and Treatment of Relapse after Allogeneic Transplantatio
Biol. Blood Marrow Transplant.
PUBLISHED: 08-24-2013
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In the Second Annual National Cancer Institutes Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Prevention and Treatment of Relapse after Allogeneic Transplantation highlighted progress in developing new therapeutic approaches since the first relapse workshop. Recent insights that might provide a basis for the development of novel, practical clinical trials were emphasized, including utilization of newer agents, optimization of donor lymphocyte infusion (DLI), and investigation of novel cellular therapies. Dr. de Lima discussed pre-emptive and maintenance strategies to prevent relapse after transplantation, for example, recent promising results suggestive of enhanced graft-versus-tumor activity with hypomethylating agents. Dr. Schmid provided an overview of adjunctive strategies to improve cell therapy for relapse, including cytoreduction before DLI, combination of targeted agents with DLI, and considerations in use of second transplantations. Dr. Porter addressed strategies to enhance T cell function, including ex vivo activated T cells and T cell engineering, and immunomodulatory approaches to enhance T cell function in vivo, including exogenous cytokines and modulation of costimulatory pathways.
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A comprehensive update on current fixation options for two-part proximal humerus fractures: A biomechanical investigation.
Injury
PUBLISHED: 07-08-2013
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Recent advancements in implant technology offer updated options for surgical management that have been rapidly adopted into clinical practice. The objective of this study is to biomechanically test and compare the current fixation options available for surgical fixation of two-part proximal humerus fractures and establish load to failure and stiffness values.
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The impact behaviour of silk cocoons.
J. Exp. Biol.
PUBLISHED: 06-28-2013
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Silk cocoons, constructed by silkmoths (Lepidoptera), are protective structural composites. Some cocoons appear to have evolved towards structural and material optimisation in order to sustain impact strikes from predators and hinder parasite ingress. This study investigates the protective properties of silk cocoons with different morphologies by evaluating their impact resistance and damage tolerance. Finite element analysis was used to analyse empirical observations of the quasi-static impact response of the silk cocoons, and to evaluate the separate benefits of the structures and materials through the deformation and damage mechanism. We use design principles from composite engineering in order to understand the structure-property-function relationship of silkworm cocoons. Understanding the highly evolved survival strategies of the organisms building natural cocoons will hopefully lead to inspiration that in turn could lead to improved composite design.
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3D Multi-slab diffusion-weighted readout-segmented EPI with real-time cardiac-reordered k-space acquisition.
Magn Reson Med
PUBLISHED: 04-19-2013
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The aim of this study was to develop, implement, and demonstrate a three-dimensional (3D) extension of the readout-segmented echo-planar imaging (rs-EPI) sequence for diffusion imaging.
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Soft-tissue Sarcomas in the Asia-Pacific Region: A Systematic Review.
Asian Pac. J. Cancer Prev.
PUBLISHED: 04-09-2013
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Background: Soft-tissue sarcomas require tailored and multidisciplinary treatment and management. However, little is known about how sarcomas are treated and managed throughout the Asia-Pacific region. Materials and Methods: MEDLINE was systematically searched using prespecified criteria. Publications (previous 10 years) that reported tumour characteristics, treatment patterns, survival outcomes, and/or safety outcomes of patients with soft-tissue sarcoma were selected. Exclusion criteria were studies of patients <18 years of age; ?10 patients; countries other than Australia, Hong Kong, Indonesia, Korea, Malaysia, New Zealand, Philippines, Singapore, Taiwan, or Thailand; >20% benign tumours; sarcomas located in bones or joints; gastrointestinal stromal tumour; Kaposis sarcoma; or not reporting relevant outcomes. Results: Of the 1,822 publications retrieved, 35 (32 studies) were included. Nearly all patients (98%, 1,992/2,024; 31 studies) were treated with surgery, and more studies used adjuvant radiotherapy than chemotherapy (24 vs 17 studies). Survival outcomes and recurrence rates varied among the studies because of the different histotypes, sites, and disease stages assessed. Only 5 studies reported safety findings. Conclusions: These findings highlight the lack of specific data available about soft-tissue sarcomas in the Asia-Pacific region. Better efforts to understand how the sarcoma is managed and treated will help improve patient outcomes in the region.
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Comparison of modeling methods to determine liver-to-blood inocula and parasite multiplication rates during controlled human malaria infection.
J. Infect. Dis.
PUBLISHED: 04-09-2013
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Controlled human malaria infection is used to measure efficacy of candidate malaria vaccines before field studies are undertaken. Mathematical modeling using data from quantitative polymerase chain reaction (qPCR) parasitemia monitoring can discriminate between vaccine effects on the parasites liver and blood stages. Uncertainty regarding the most appropriate modeling method hinders interpretation of such trials. We used qPCR data from 267 Plasmodium falciparum infections to compare linear, sine-wave, and normal-cumulative-density-function models. We find that the parameters estimated by these models are closely correlated, and their predictive accuracy for omitted data points was similar. We propose that future studies include the linear model.
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Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
N. Engl. J. Med.
PUBLISHED: 03-25-2013
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Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
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Receipt of maintenance therapy is most predictive of survival in older acute lymphoblastic leukemia patients treated with intensive induction chemotherapy regimens.
Am. J. Hematol.
PUBLISHED: 03-02-2013
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While the prognosis for older adults diagnosed with acute lymphoblastic leukemia (ALL) is frequently poor, long-term survival can be achieved in patients treated with curative intent. We reviewed the outcomes of 37 patients age ?60 treated at our institution with either DVP- or hyperCVAD-based chemotherapy regimens from 2003-2011. In this patient population, a complete response rate of 92%, relapse rate of 56% and median overall survival of 18.1 months was experienced. Univariate analysis revealed that receipt of maintenance therapy vs. no maintenance therapy was associated with a statistically-significant impact on overall survival (p = 0.001, HR 0.15 for death), while disease-related characteristics including high-risk white blood cell count at diagnosis and Philadelphia chromosome status as well as treatment-related factors including chemotherapy regimen or completion of intensive therapy were not. Many patients were unable to initiate or remain on maintenance therapy due to toxicities including infections and cytopenias. Our analysis reveals the benefit of prolonged therapy in the treatment of older adults with ALL as well as the high incidence of treatment-related toxicity experienced by these patients.
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High-resolution diffusion-weighted imaging for the separation of benign from malignant BI-RADS 4/5 lesions found on breast MRI at 3T.
J Magn Reson Imaging
PUBLISHED: 02-25-2013
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To determine whether readout-segmented echo-planar diffusion imaging (RESOLVE) improves separation of malignant versus benign lesions compared to standard single-shot echo-planar imaging (ss-EPI) on BI-RADS 4/5 lesions detected on breast magnetic resonance imaging (MRI).
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Thermally induced changes in dynamic mechanical properties of native silks.
Biomacromolecules
PUBLISHED: 02-20-2013
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Dynamic mechanical thermal analysis (DMTA) on individual native silk fibers demonstrates changes in the dynamic mechanical properties of storage modulus and loss tangent as a function of temperature and temperature history ranging from -100 to 250 °C. These property changes are linked quantitatively to two main types of change in the silk structure. First, the evaporation of water with increasing temperature up to 100 °C increases the storage modulus and removes two characteristic loss tangent peaks at -60 and +60 °C. Second, various discrete loss tangent peaks in the range 150-220 °C are associated with specific disordered silk structures that are removed or converted to a limiting high-temperature relaxed structure by the combination of increasing temperature and static load in the DMTA tests. The results identify important origins of silk filament quality based on the analysis of measurements that can be traced back to differences in production and processing history.
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Pilot study of prophylactic ex vivo costimulated donor leukocyte infusion after reduced-intensity conditioned allogeneic stem cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-06-2013
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Donor leukocyte infusion (DLI) can induce potent graft-versus-leukemia (GVL) activity in patients with relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT). Unfortunately, except in patients with chronic-phase chronic myelogenous leukemia, responses to DLI have been disappointing. GVL induction is likely to be most effective in the setting of minimal residual disease. Prevention of relapse through the provision of prophylactic DLI to high-risk patients may improve the outcome of allogeneic HSCT. We previously reported that ex vivo costimulated T cell infusion of activated DLI (aDLI) as treatment for relapse is safe and has potent GVL effects. We hypothesized that prophylactic aDLI can be given safely and prevent relapse in high-risk patients after allogeneic HSCT. Eighteen patients with acute myeolgenous leukemia (n = 14), acute lymphoblastic leukemia (n = 3), or myelodysplastic syndrome (n = 1) underwent allogeneic HSCT after a reduced-intensity conditioning (RIC) regimen with alemtuzumab, fludarabine, and busulfan. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate with a planned early and rapid taper of tacrolimus. Patients without GVHD, off immune suppression, and in remission received aDLI at a dose of 1 × 10(7) CD3(+) cells/kg (aDLI 1) at day +120, followed by a second infusion of 1 × 10(8) CD3 cells/kg (aDLI 2) at day +180. At a median follow-up of 58 months, 5 of the 18 patients (28%) were alive, and 4 patients were in remission. Eleven patients (65%) relapsed, at a median time of 191 days. Twelve of the 18 patients received at least one aDLI, and 6 of these 12 patients also received aDLI 2. Six patients did not receive any aDLI owing to early relapse (n = 2), protocol ineligibility (n = 1), or GVHD (n = 3). Only 2 of the 12 patients who received aDLI 1 developed GVHD. Two out of the 12 patients remain in remission at the time of this report. Disease recurrence was the cause of death in 10 of the 13 patients (77%) who died. Our data indicate that prophylactic ex vivo costimulated CD3/CD28 DLI is safe, feasible, and not associated with significant GVHD. Relapse remains the major cause of treatment failure after RIC HSCT even with rapid withdrawal of immune suppression and the use of prophylactic aDLI, and better strategies to prevent relapse are needed.
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Effect of B-value in revealing postinfarct myocardial microstructural remodeling using MR diffusion tensor imaging.
Magn Reson Imaging
PUBLISHED: 01-15-2013
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Nonmonoexponential diffusion behavior has been previously reported to exist in some biological tissues, making quantification of diffusion tensor imaging (DTI) indices dependent on diffusion sensitivity of b-value. This study aims to investigate the effect of b-value in revealing postinfarct myocardial microstructural remodeling in ex vivo hearts. DTI scans were performed on heart samples 1, 3, 5, and 7 days after infarction induction as well as intact controls with b-values of 500 to 2500s/mm(2). DTI indices, including fractional anisotropy (FA), and mean and directional diffusivities, were measured in infarct, adjacent and remote regions with zero and each non-zero b-values respectively using conventional DTI analysis. Experimental results showed that these DTI indices decreased gradually with b-values in all regions and groups. Optimal b-values were found to vary with targeted DTI indices, and could strengthen DTI ability in revealing myocardium degradation with using conventional DTI approach. Specifically, FA showed the most sensitive detection of fiber integrity degradation at moderate b-values (?1500 to 2000s/mm(2)), and the greatest ability of mean and directional diffusivities in monitoring diffusivity alteration occurred at relatively small b-values (?1500s/mm(2)) during the necrotic and fibrotic phases. These findings may provide useful information for DTI protocol parameter optimization in assessing heart microstructures at other pathological or in vivo states in the future.
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Clinical evaluation of single-shot and readout-segmented diffusion-weighted imaging in stroke patients at 3 T.
Acta Radiol
PUBLISHED: 01-14-2013
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Diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) is most commonly performed utilizing a single-shot echo-planar imaging technique (ss-EPI). Susceptibility artifact and image blur are severe when this sequence is utilized at 3 T.
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Time-optimized high-resolution readout-segmented diffusion tensor imaging.
PLoS ONE
PUBLISHED: 01-01-2013
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Readout-segmented echo planar imaging with 2D navigator-based reacquisition is an uprising technique enabling the sampling of high-resolution diffusion images with reduced susceptibility artifacts. However, low signal from the small voxels and long scan times hamper the clinical applicability. Therefore, we introduce a regularization algorithm based on total variation that is applied directly on the entire diffusion tensor. The spatially varying regularization parameter is determined automatically dependent on spatial variations in signal-to-noise ratio thus, avoiding over- or under-regularization. Information about the noise distribution in the diffusion tensor is extracted from the diffusion weighted images by means of complex independent component analysis. Moreover, the combination of those features enables processing of the diffusion data absolutely user independent. Tractography from in vivo data and from a software phantom demonstrate the advantage of the spatially varying regularization compared to un-regularized data with respect to parameters relevant for fiber-tracking such as Mean Fiber Length, Track Count, Volume and Voxel Count. Specifically, for in vivo data findings suggest that tractography results from the regularized diffusion tensor based on one measurement (16 min) generates results comparable to the un-regularized data with three averages (48 min). This significant reduction in scan time renders high resolution (1 × 1 × 2.5 mm(3)) diffusion tensor imaging of the entire brain applicable in a clinical context.
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Allogeneic immunotherapy to optimize the graft-versus-tumor effect: concepts and controversies.
Hematology Am Soc Hematol Educ Program
PUBLISHED: 12-14-2011
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Allogeneic stem cell transplantation (SCT) can be considered the most successful method of adoptive immunotherapy of cancer. It is successful in part because of the potent graft-versus-tumor (GVT) effects of the donor graft, which are independent of the conditioning regimen. This potent GVT reaction can be harnessed in some cases to treat patients who relapse after allogeneic SCT with the use of donor leukocyte infusions (DLIs). This has led to the rapid development of reduced-intensity conditioning (RIC) regimens for allogeneic SCT, an approach that relies primarily on GVT activity. However, the effects of GVT have clear disease specificity and remain associated with significant GVHD. Optimization of GVT induction will require a better understanding of the important target antigens and effector cells, as well as the development of methods that enhance GVT reactivity without excessive GVHD. The appropriate clinical setting and timing for GVT induction need to be defined more clearly, but ultimately, the immunologic control of cancer through allogeneic adoptive immunotherapy represents one of the most potent and promising therapeutic strategies for patients with hematologic malignancies.
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Cellular therapy following allogeneic stem-cell transplantation.
Ther Adv Hematol
PUBLISHED: 12-01-2011
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Allogeneic hematopoietic stem-cell transplantation (HSCT) is the most effective approach for many patients with hematologic malignancies. Unfortunately, relapse remains the most common cause of death after allogeneic HSCT, and the prognosis of relapsed disease is poor for most patients. Induction of a graft-versus-leukemia (GVL), or graft-versus-tumor, effect through the use of donor leukocyte infusion (DLI), or donor lymphocyte infusion, has been remarkably successful for relapsed chronic myelogenous leukemia. Unfortunately, response to DLI in other hematologic malignancies is much less common and depends on many factors including histology, pace and extent of relapse, and time from HSCT to relapse. Furthermore, graft-versus-host disease (GVHD) is common after DLI and often limits successful immunotherapy. Ultimately, manipulations to minimize GVHD while preserving or enhancing GVL are necessary to improve outcomes for relapse after allogeneic HSCT.
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T cell-depleted partial matched unrelated donor transplant for advanced myeloid malignancy: KIR ligand mismatch and outcome.
Biol. Blood Marrow Transplant.
PUBLISHED: 10-04-2011
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To evaluate the applicability of high-dose conditioning, CD34 selection, and enhanced natural killer (NK) cell alloreactivity reported as promising after haploidentical transplantation, we tested the same strategy for patients with advanced/high-risk myeloid leukemia lacking either related or well-matched unrelated donors (URD). In a prospective multicenter clinical trial using pretransplantation conditioning of thiotepa (5 mg/kg/day × 2), fludarabine (40 mg/mg/M(2)/day × 5), and total body radiation (800 cGy) plus thymoglobulin (2.5 mg/kg/day × 2), as well as a CD34 selected filgrastim stimulated peripheral blood graft from a partial matched URD, we treated 24 patients. The patients (median age 40 [range: 22-61]) were mismatched at 1-3 of 10 HLA loci with their donors; all were mismatched at HLA-C. Thirty-seven percent were ethnic or racial minorities. Twenty-one of 24 engrafted promptly with 1 primary graft failure and 2 early deaths. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) (34%, 95% confidence interval [CI], 14-54%), chronic GVHD (20%, 95% CI, 2%-38%), and relapse (26%, 95% CI, 8%-84%) were unaffected by KIR ligand donor:recipient mismatch (n = 5) versus KIR ligand match (n = 19). Only 3 (12%) had grade III-IV GVHD. Nonrelapse occurred in 17% (95% CI, 30%-31%) by 100 days and in 35% (95% CI, 15%-55%) by 1 year. Two-year survival and leukemia-free survival were each 40% (95% CI, 21%-59%) and was similar in KIR ligand matched or mismatched patients. Infections, mostly in the first 2 months, were frequent, and were the cause of death in 5 patients (35% of deaths). T cell recovery and NK cell proliferation and functional maturation were not altered by KIR ligand match or mismatch status. For these high-risk patients, this high intensity regimen and T depleted approach yielded satisfactory outcomes, but logistical difficulties in arranging URD grafts for patients with high-risk, unstable leukemia limited accrual. Improvements in peritransplantation disease control and additional measures to augment the allogeneic graft-versus-leukemia effect are still required.
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Sitting playfully: does the use of a centre of gravity computer game controller influence the sitting ability of young people with cerebral palsy?
Disabil Rehabil Assist Technol
PUBLISHED: 10-04-2011
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An investigative study to examine whether sitting ability could be improved through the use of a suite of computer games operated by leaning in one of four directions in a seated position. MethOD: Young people with cerebral palsy played with a suite of computer games controlled using a sitting platform that can detect changes in the distribution of pressure. A randomized cross-over trial with two periods of three months involving intervention or no intervention was used. Sitting ability was measured at the beginning and end of each period with participants acting as their own controls.
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Two mechanisms for supercontraction in Nephila spider dragline silk.
Biomacromolecules
PUBLISHED: 10-04-2011
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Supercontraction in dragline silk of Nephila edulis spider is shown to have two distinct components revealed by single fiber measurements using dynamic mechanical thermal analysis. The first component relies on a contraction of maximum 13% and seems to be associated with relaxation processed through the glass transition, T(g), as is induced by increasing temperature and/or humidity. The second component is induced by liquid water to the total contraction of 30%. The T(g)-induced contraction is linearly correlated with the restraining stress on the fiber, and the mechanical properties of the partially contracted silk have mechanical profiles that differ from both native and fully supercontracted fibers. Here we present novel supercontraction data and discuss their structural origins, examining the relaxation of stretched orientation in the different primary structure sequences.
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T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.
Sci Transl Med
PUBLISHED: 08-12-2011
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Tumor immunotherapy with T lymphocytes, which can recognize and destroy malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials. We report that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ? chain have potent non-cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL). The engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months. Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia. On average, each infused CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells. Furthermore, a CD19-specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission, in two of three patients. Moreover, a portion of these cells persisted as memory CAR(+) T cells and retained anti-CD19 effector functionality, indicating the potential of this major histocompatibility complex-independent approach for the effective treatment of B cell malignancies.
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Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.
N. Engl. J. Med.
PUBLISHED: 08-10-2011
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We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.
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An inter-laboratory validation of a real time PCR assay to measure host excretion of bacterial pathogens, particularly of Mycobacterium bovis.
PLoS ONE
PUBLISHED: 08-05-2011
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Advances in the diagnosis of Mycobacterium bovis infection in wildlife hosts may benefit the development of sustainable approaches to the management of bovine tuberculosis in cattle. In the present study, three laboratories from two different countries participated in a validation trial to evaluate the reliability and reproducibility of a real time PCR assay in the detection and quantification of M. bovis from environmental samples. The sample panels consisted of negative badger faeces spiked with a dilution series of M. bovis BCG Pasteur and of field samples of faeces from badgers of unknown infection status taken from badger latrines in areas with high and low incidence of bovine TB (bTB) in cattle. Samples were tested with a previously optimised methodology. The experimental design involved rigorous testing which highlighted a number of potential pitfalls in the analysis of environmental samples using real time PCR. Despite minor variation between operators and laboratories, the validation study demonstrated good concordance between the three laboratories: on the spiked panels, the test showed high levels of agreement in terms of positive/negative detection, with high specificity (100%) and high sensitivity (97%) at levels of 10(5) cells g(-1) and above. Quantitative analysis of the data revealed low variability in recovery of BCG cells between laboratories and operators. On the field samples, the test showed high reproducibility both in terms of positive/negative detection and in the number of cells detected, despite low numbers of samples identified as positive by any laboratory. Use of a parallel PCR inhibition control assay revealed negligible PCR-interfering chemicals co-extracted with the DNA. This is the first example of a multi-laboratory validation of a real time PCR assay for the detection of mycobacteria in environmental samples. Field studies are now required to determine how best to apply the assay for population-level bTB surveillance in wildlife.
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Drop metastases to the pediatric spine revealed with diffusion-weighted MR imaging.
Pediatr Radiol
PUBLISHED: 07-11-2011
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Identifying drop metastases to the spine from pediatric brain tumors is crucial to treatment and prognosis. MRI is currently the gold standard for identifying drop metastases, more sensitive than CSF cytology, but imaging is not uncommonly inconclusive. Although diffusion-weighted imaging (DWI) of the brain is very useful in the evaluation of hypercellular tumors, DWI of the spine has not been clinically useful in children because of susceptibility artifacts and lack of spatial resolution. A new technique, readout-segmented echo planar imaging (EPI), has improved these images, allowing for identification of hypercellular drop metastases. We report a case that illustrates the utility of spine DWI in the detection of metastatic disease in children with primary central nervous system (CNS) tumors. This case suggests that DWI of the spine with readout-segmented EPI should be included in the evaluation for drop metastases.
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Vitamin D status of adults from tropical Australia determined using two different laboratory assays: implications for public health messages.
Photochem. Photobiol.
PUBLISHED: 06-13-2011
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We measured serum 25 hydroxyvitamin D [25(OH)D] levels of ambulatory adults in tropical Australia to determine whether it is appropriate to continue promoting sun-safety in this population. In August 2006 (winter), self-administered questionnaires were completed by 145 Meals-on-Wheels volunteers (49.3% male; mean age 57.8 ± 14.7 years; 76.6% response) from Townsville, Queensland (Latitude 19(o) S). Serum 25(OH)D was analyzed using two common assays. Mean levels were 68.3 (SD ± 18.7; range 26-142) by DiaSorin Radioimmunoassay and 83.0 (SD ± 30.8; range 30-184) by DiaSorin Liaison® one. No participants were 25(OH)D deficient (<25 nmol L(-1)). Nine participants (6.2%) had 25(OH)D levels between 25 and 50 nmol L(-1) (insufficient), by both methods (seven with a BMI ? 25). Twenty-eight participants (19.3%) had one result in the insufficient range and the other in the adequate range. Thus, almost all of these free-living adults in tropical Australia had adequate vitamin D levels at the end of winter. There was poor agreement between the two 25(OH)D assays. These results suggest it is appropriate to continue promoting sun-safe messages to the ambulatory Caucasian adult population of North Queensland, which has an extremely high incidence of skin cancer. The lack of agreement between the two assays is a concern. Few doctors are aware of this measurement issue.
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Spontaneous regression of a third ventricle colloid cyst.
Br J Neurosurg
PUBLISHED: 05-18-2011
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We present a case of a third ventricle colloid cyst in a 65-year-old patient who was managed conservatively with neuroimaging surveillance. To our surprise, the cyst underwent spontaneous regression 19 months after initial diagnosis. To our knowledge there has only been one similar case previously reported in Glasgow, United Kingdom in 2008.
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Implementation and assessment of diffusion-weighted partial Fourier readout-segmented echo-planar imaging.
Magn Reson Med
PUBLISHED: 05-10-2011
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Single-shot echo-planar imaging has been used widely in diffusion magnetic resonance imaging due to the difficulties in correcting motion-induced phase corruption in multishot data. Readout-segmented EPI has addressed the multishot problem by introducing a two-dimensional nonlinear navigator correction with online reacquisition of uncorrectable data to enable acquisition of high-resolution diffusion data with reduced susceptibility artifact and T*(2) blurring. The primary shortcoming of readout-segmented EPI in its current form is its long acquisition time (longer than similar resolution single-shot echo-planar imaging protocols by approximately the number of readout segments), which limits the number of diffusion directions. By omitting readout segments at one side of k-space and using partial Fourier reconstruction, readout-segmented EPI imaging times could be reduced. In this study, the effects of homodyne and projection onto convex sets reconstructions on estimates of the fractional anisotropy, mean diffusivity, and diffusion orientation in fiber tracts and raw T(2)- and trace-weighted signal are compared, along with signal-to-noise ratio results. It is found that projections onto convex sets reconstruction with 3/5 segments in a 2 mm isotropic diffusion tensor image acquisition and 9/13 segments in a 0.9 × 0.9 × 4.0 mm(3) diffusion-weighted image acquisition provide good fidelity relative to the full k-space parameters. This allows application of readout-segmented EPI to tractography studies, and clinical stroke and oncology protocols.
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An inhibitor of eIF2 activity in the sRNA pool of eukaryotic cells.
Gene
PUBLISHED: 05-05-2011
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Eukaryotic protein synthesis is a multi-step and highly controlled process that includes an early initiation complex containing eukaryotic initiation factor 2 (eIF2), GTP, and methionine-charged initiator methionyl-tRNA (met-tRNAi). During studies to reconstruct formation of the ternary complex containing these molecules, we detected a potent inhibitor in low molecular mass RNA (sRNA) preparations of eukaryotic tRNA. The ternary complex inhibitor (TCI) was retained in the total sRNA pool after met-tRNAi was charged by aminoacyl tRNA synthetase, co-eluted with sRNA by size exclusion chromatography, but resolved from met-tRNAi by ion exchange chromatography. The adverse effect of TCI was not overcome by high GTP or magnesium omission and was independent of GTP regeneration. Rather, TCI suppressed the rate of ternary complex formation, and disrupted protein synthesis and the accumulation of heavy polymeric ribosomes in reticulocyte lysates in vitro. Lastly, a component or components in ribosome depleted cell lysate significantly reversed TCI activity. Since assembly of the met-tRNAi/eIF2/GTP ternary complex is integral to protein synthesis, awareness of TCI is important to avoid confusion in studies of translation initiation. A clear definition of TCI may also allow a better appreciation of physiologic or pathologic situations, factors, and events that control protein synthesis in vivo.
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Chimeric Antigen Receptor Therapy for B-cell Malignancies.
J Cancer
PUBLISHED: 04-21-2011
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We presented data showing that the CART-19 cells expressing the 4-1BB signaling domain can have unprecedented and massive in-vivo expansion, traffic to tumor sites, persist long term in vivo, and induce rapid and potent anti-tumor activity in chemotherapy refractory CLL patients.
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Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies.
Blood
PUBLISHED: 04-04-2011
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The success of reduced intensity conditioning (RIC) transplantation is largely dependent on alloimmune effects. It is critical to determine whether immune modulation with anti-T-cell antibody infusion abrogates the therapeutic benefits of transplantation. We examined 1676 adults undergoing RIC transplantation for hematologic malignancies. All patients received alkylating agent plus fludarabine; 792 received allografts from a human leukocyte antigen-matched sibling, 884 from a 7 or 8 of 8 HLA-matched unrelated donor. Using Cox regression, outcomes after in vivo T-cell depletion (n = 584 antithymocyte globulin [ATG]; n = 213 alemtuzumab) were compared with T cell- replete (n = 879) transplantation. Grade 2 to 4 acute GVHD was lower with alemtuzumab compared with ATG or T cell- replete regimens (19% vs 38% vs 40%, P < .0001) and chronic GVHD, lower with alemtuzumab, and ATG regimens compared with T-replete approaches (24% vs 40% vs 52%, P < .0001). However, relapse was more frequent with alemtuzumab and ATG compared with T cell-replete regimens (49%, 51%, and 38%, respectively, P < .001). Disease-free survival was lower with alemtuzumab and ATG compared with T cell-replete regimens (30%, 25%, and 39%, respectively, P < .001). Corresponding probabilities of overall survival were 50%, 38%, and 46% (P = .008). These data suggest adopting a cautious approach to routine use of in vivo T-cell depletion with RIC regimens.
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Pathogen quantitation in complex matrices: a multi-operator comparison of DNA extraction methods with a novel assessment of PCR inhibition.
PLoS ONE
PUBLISHED: 02-15-2011
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Mycobacterium bovis is the aetiological agent of bovine tuberculosis (bTB), an important recrudescent zoonosis, significantly increasing in British herds in recent years. Wildlife reservoirs have been identified for this disease but the mode of transmission to cattle remains unclear. There is evidence that viable M. bovis cells can survive in soil and faeces for over a year.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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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.