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Find video protocols related to scientific articles indexed in Pubmed.
A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL-6 mAb) and Bortezomib versus Bortezomib Alone in Patients with Relapsed or Refractory Multiple Myeloma.
Am. J. Hematol.
PUBLISHED: 10-01-2014
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We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc)+B in patients with relapsed/refractory multiple myeloma in a randomized phase II study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by EBMT criteria. For the 281 randomized patients, median PFS for S+B and plc+B was 8.0 and 7.6 months (HR 0.869, p=0.345), overall response rate was 55% vs. 47% (p=0.213), complete response rate was 11% vs. 7%, and median overall survival (OS) was 30.8 vs. 36.8 months (HR 1.353, p=0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S+B. Siltuximab did not affect B pharmacokinetics. S/plc discontinuation (75% vs. 66%), grade ?3 neutropenia (49% vs. 29%), thrombocytopenia (48% vs. 34%), and all-grade infections (62% vs. 49%) occurred more frequently with S+B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma.
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Multi-Technique Characterization of Poly-L-lysine Dendrigrafts-Cu(II) Complexes for Biocatalysis.
Macromol Biosci
PUBLISHED: 07-24-2014
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Poly-L-lysine is a biocompatible polymer used for drug or gene delivery, for transport through cellular membranes, and as nanosized magnetic resonance imaging contrast agents. Cu(II)-poly-L-lysine complexes are of particular interest for their role in biocatalysis. In this study, poly-L-lysine dendrigrafts (DGLs) at different generations (G2, G3, and G4) are synthesized and characterized in absence and presence of Cu(II) by means of electron paramagnetic resonance (EPR), UV-Vis, potentiometric titration and circular dichroism (CD). The analysis is performed as a function of the [Cu(II)]/[Lys] (=R) molar ratio, pH and generation by identifying differently flexible complexes in different dendrimer regions. The amine sites in the lateral chains become increasingly involved with the increase of pH. The good agreement and complementarity of the results from the different techniques provide an integrate view of the structural and dynamic properties of Cu(II)-DGL complexes implementing their use as biocatalysts.
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Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.
Lancet Oncol.
PUBLISHED: 07-17-2014
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Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease.
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Diastereoselectivity in prebiotically relevant 5(4H)-oxazolone-mediated peptide couplings.
Chem. Commun. (Camb.)
PUBLISHED: 02-11-2014
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A stereochemical study of a potentially prebiotic peptide-forming reaction was carried out as the first part of a systems chemistry investigation of potential paths for symmetry breaking. Substantial diastereomeric excesses result from a fast epimerization of the 5(4H)-oxazolone intermediate in aqueous solution.
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All-trans retinoic acid (ATRA) induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity.
Int. J. Biochem. Cell Biol.
PUBLISHED: 01-02-2014
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NK cell is an innate immune system lymphocyte lineage with natural cytotoxicity. Its optimal use in the clinic requires in vitro expansion and activation. Cytokines and encounter with target cells activate NK cells and induce proliferation, and this could depend on the presence of other immune cells. Here we activated PBMCs during 5 days with IL-2, with IL-2 plus the tumor cell line K562 and with the lymphoblastoid cell line R69 and perform integrated analyses of microRNA and mRNA expression profiles of purified NK cells. The samples cluster depending on the stimuli and not on the donor, indicating that the pattern of NK cell stimulation is acutely well conserved between individuals. Regulation of mRNA expression is tighter than that of miRNA expression. All stimuli induce a common preserved genetic remodeling. In addition, encounter with target cells mainly activates pathways related to metabolism. Different target cells induce different NK cell remodeling which affects cytokine response and cytotoxicity, supporting the notion that encounter with different target cells significantly changing the activation pattern. We validate our analysis by showing that activation down regulates miR-23a, which is a negative regulator of cathepsin C (CTSC) mRNA, a gene up regulated by all stimuli. The peptidase CTSC activates the granzymes, the main effector proteases involved in NK cell cytotoxicity. All-trans retinoic acid (ATRA), which induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity in an in vivo mouse model.
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Controlled Epstein-Barr virus reactivation after allogeneic transplantation is associated with improved survival.
Eur. J. Haematol.
PUBLISHED: 01-02-2014
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Epstein-Barr virus reactivation (EBV-R) frequently occurs in patients having allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the impact of controlled EBV-R on survival of 190 patients (114M/76F, median age: 51 yr, range 18-69), having HSCT for hematological malignancies (105 acute leukemias and myelodysplasias, 71 lymphoproliferative disorders, 14 others). Overall survival (OS) and progression-free survival (PFS) were compared between patients with and without EBV-R. Of 138, patients had reduced-intensity conditioning regimen. Various stem cell sources (141 PB, 33 umbilical cord blood and 16 bone marrow) were used. Patients with EBV-R had longer PFS and OS than those without EBV-R: PFS at 2 yr 69% vs. 51% and at 5 yr 47% vs. 38% (P < 0.04); OS at 2 yr 76% vs. 64% and at 5 yr 63% vs. 47%) (P < 0.001). The use of rituximab had no impact on OS and PFS, but it reduced the intensity of GVHD, despite the fact that TRM was not significantly different between the two groups of patients. So, rituximab may have an additional effect to other factors on PFS and OS. In multivariate analysis, antithymocyte globulin administration was not a significant factor for PFS (P = 0.68) and for OS (P = 0.81). Circulating NK cells were significantly increased by 22% (P = 0.03) in EBV-R patients with no differences for other parameters. Controlled EBV-R in the setting of HSCT is associated with better OS and PFS, with a significant increase in circulating NK cells.
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Spatial Segregation between Invasive and Native Commensal Rodents in an Urban Environment: A Case Study in Niamey, Niger.
PLoS ONE
PUBLISHED: 01-01-2014
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Invasive rodents have been responsible for the diffusion worldwide of many zoonotic agents, thus representing major threats for public health. Cities are important hubs for people and goods exchange and are thus expected to play a pivotal role in invasive commensal rodent dissemination. Yet, data about urban rodents' ecology, especially invasive vs. native species interactions, are dramatically scarce. Here, we provide results of an extensive survey of urban rodents conducted in Niamey, Niger, depicting the early stages of rodent bioinvasions within a city. We explore the species-specific spatial distributions throughout the city using contrasted approaches, namely field sampling, co-occurrence analysis, occupancy modelling and indicator geostatistics. We show that (i) two species (i.e. rural-like vs. truly commensal) assemblages can be identified, and that (ii) within commensal rodents, invasive (Rattus rattus and Mus musculus) and native (Mastomys natalensis) species are spatially segregated. Moreover, several pieces of arguments tend to suggest that these exclusive distributions reflect an ongoing native-to-invasive species turn over. The underlying processes as well as the possible consequences for humans are discussed.
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Dissecting the space-time structure of tree-ring datasets using the partial triadic analysis.
PLoS ONE
PUBLISHED: 01-01-2014
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Tree-ring datasets are used in a variety of circumstances, including archeology, climatology, forest ecology, and wood technology. These data are based on microdensity profiles and consist of a set of tree-ring descriptors, such as ring width or early/latewood density, measured for a set of individual trees. Because successive rings correspond to successive years, the resulting dataset is a ring variables × trees × time datacube. Multivariate statistical analyses, such as principal component analysis, have been widely used for extracting worthwhile information from ring datasets, but they typically address two-way matrices, such as ring variables × trees or ring variables × time. Here, we explore the potential of the partial triadic analysis (PTA), a multivariate method dedicated to the analysis of three-way datasets, to apprehend the space-time structure of tree-ring datasets. We analyzed a set of 11 tree-ring descriptors measured in 149 georeferenced individuals of European larch (Larix decidua Miller) during the period of 1967-2007. The processing of densitometry profiles led to a set of ring descriptors for each tree and for each year from 1967-2007. The resulting three-way data table was subjected to two distinct analyses in order to explore i) the temporal evolution of spatial structures and ii) the spatial structure of temporal dynamics. We report the presence of a spatial structure common to the different years, highlighting the inter-individual variability of the ring descriptors at the stand scale. We found a temporal trajectory common to the trees that could be separated into a high and low frequency signal, corresponding to inter-annual variations possibly related to defoliation events and a long-term trend possibly related to climate change. We conclude that PTA is a powerful tool to unravel and hierarchize the different sources of variation within tree-ring datasets.
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Tumor cells in multiple myeloma patients inhibit myeloma-reactive T cells through carcinoembryonic antigen-related cell adhesion molecule-6.
Blood
PUBLISHED: 04-19-2013
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Although functionally competent cytotoxic, T cells are frequently observed in malignant diseases, they possess little ability to react against tumor cells. This phenomenon is particularly apparent in multiple myeloma. We here demonstrate that cytotoxic T cells reacted against myeloma antigens when presented by autologous dendritic cells, but not by myeloma cells. We further show by gene expression profiling and flow cytometry that, similar to many other malignant tumors, freshly isolated myeloma cells expressed several carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) at varying proportions. Binding and crosslinking of CEACAM-6 by cytotoxic T cells inhibited their activation and resulted in T-cell unresponsiveness. Blocking of CEACAM-6 on the surface of myeloma cells by specific monoclonal antibodies or CEACAM-6 gene knock down by short interfering RNA restored T-cell reactivity against malignant plasma cells. These findings suggest that CEACAM-6 plays an important role in the regulation of CD8+ T-cell responses against multiple myeloma; therefore, therapeutic targeting of CEACAM-6 may be a promising strategy to improve myeloma immunotherapy.
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Toxoplasmosis seroprevalence in urban rodents: a survey in Niamey, Niger.
Mem. Inst. Oswaldo Cruz
PUBLISHED: 04-12-2013
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A serological survey of Toxoplasma gondii was conducted on 766 domestic and peridomestic rodents from 46 trapping sites throughout the city of Niamey, Niger. A low seroprevalence was found over the whole town with only 1.96% of the rodents found seropositive. However, differences between species were important, ranging from less than 2% in truly commensal Mastomys natalensis, Rattus rattus and Mus musculus, while garden-associated Arvicanthis niloticus displayed 9.1% of seropositive individuals. This is in line with previous studies on tropical rodents--that we reviewed here--which altogether show that Toxoplasma seroprevalence in rodent is highly variable, depending on many factors such as locality and/or species. Moreover, although we were not able to decipher statistically between habitat or species effect, such a contrast between Nile grass rats and the other rodent species points towards a potentially important role of environmental toxoplasmic infection. This would deserve to be further scrutinised since intra-city irrigated cultures are extending in Niamey, thus potentially increasing Toxoplasma circulation in this yet semi-arid region. As far as we are aware of, our study is one of the rare surveys of its kind performed in Sub-Saharan Africa and the first one ever conducted in the Sahel.
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Assessing species distribution using Google street view: a pilot study with the Pine Processionary Moth.
PLoS ONE
PUBLISHED: 01-01-2013
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Mapping species spatial distribution using spatial inference and prediction requires a lot of data. Occurrence data are generally not easily available from the literature and are very time-consuming to collect in the field. For that reason, we designed a survey to explore to which extent large-scale databases such as Google maps and Google street view could be used to derive valid occurrence data. We worked with the Pine Processionary Moth (PPM) Thaumetopoea pityocampa because the larvae of that moth build silk nests that are easily visible. The presence of the species at one location can therefore be inferred from visual records derived from the panoramic views available from Google street view. We designed a standardized procedure allowing evaluating the presence of the PPM on a sampling grid covering the landscape under study. The outputs were compared to field data. We investigated two landscapes using grids of different extent and mesh size. Data derived from Google street view were highly similar to field data in the large-scale analysis based on a square grid with a mesh of 16 km (96% of matching records). Using a 2 km mesh size led to a strong divergence between field and Google-derived data (46% of matching records). We conclude that Google database might provide useful occurrence data for mapping the distribution of species which presence can be visually evaluated such as the PPM. However, the accuracy of the output strongly depends on the spatial scales considered and on the sampling grid used. Other factors such as the coverage of Google street view network with regards to sampling grid size and the spatial distribution of host trees with regards to road network may also be determinant.
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Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program.
Blood
PUBLISHED: 08-10-2011
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Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ? 50 × 10(9)/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 10(9)/L (interquartile range, 75-167 × 10(9)/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 10(9)/L (interquartile range, 35-44 × 10(9)/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.
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Phase I study of atacicept in relapsed/refractory multiple myeloma (MM) and Waldenströms macroglobulinemia.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 04-02-2011
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Atacicept, a specific inhibitor of BLys and APRIL, was used in a phase I study for 14 patients with myeloma (MM) and 4 with Waldenströms macroglobulinemia (WM). They received 1 cycle of 5 once-weekly s.c. injections, followed by an extension if in stable disease or in response. The maximum tolerated dose was not identified. Of 11 patients with MM who completed initial treatment, 5 patients were progression-free after cycle 1 and 4 patients were progression-free after extended therapy. Of 4 patients with WM, 3 patients were progression-free after cycle 1. Polyclonal immunoglobulin isotypes and total B cells were reduced. Plasma concentrations of soluble CD 138 decreased. Biological effect was more pronounced in WM. Of the 16 patients tested at baseline, 13 had measurable levels of free APRIL (?25 ng/mL). In this small series, no correlations were apparent between baseline levels of free APRIL and biological or clinical response criteria.
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Dynamic lipid-protein stoichiometry on E1 and E2 conformations of the Na+/K+ -ATPase.
FEBS Lett.
PUBLISHED: 01-06-2011
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Annular lipid-protein stoichiometry in native pig kidney Na+/K+ -ATPase preparation was studied by [125I]TID-PC/16 labeling. Our data indicate that the transmembrane domain of the Na+/K+ -ATPase in the E1 state is less exposed to the lipids than in E2, i.e., the conformational transitions are accompanied by changes in the number of annular lipids but not in the affinity of these lipids for the protein. The lipid-protein stoichiometry was 23 ± 2 (? subunit) and 5.0 ± 0.4 (? subunit) in the E1 conformation and 32 ± 2 (? subunit) and 7 ± 1 (? subunit) in the E2 conformation.
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?? T-cell killing of primary follicular lymphoma cells is dramatically potentiated by GA101, a type II glycoengineered anti-CD20 monoclonal antibody.
Haematologica
PUBLISHED: 11-25-2010
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Anti-CD20 monoclonal antibodies are major therapeutic agents for patients with follicular lymphoma and work through complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. Optimization of antibody-dependent cellular cytotoxicity, in particular by amplifying its effectors, could further increase the efficacy of anti-CD20 monoclonal antibodies.
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Mobilization of plasma cells in healthy individuals treated with granulocyte colony-stimulating factor for haematopoietic stem cell collection.
Immunology
PUBLISHED: 10-13-2010
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In mice, the plasma cell (PC) niche in the bone marrow is close to the haematopoietic stem cell (HSC) niche. We investigated whether PCs can be mobilized into the peripheral blood (PB) in healthy donors receiving granulocyte colony-stimulating factor (G-CSF) for the induction of HSC mobilization into the PB. G-CSF increased the count of circulating PCs 6-fold, that of circulating B lymphocytes 4-fold and that of circulating HSCs 44-fold. Mobilized circulating PCs comprised CD138(-) (62·2%) and CD138(+) (37·8%) PCs, the latter being more mature based on increased CD27, CD38 and cytoplasmic immunoglobulin expression. Mobilized PCs had a phenotype close to that of steady-state PB PCs or in vitro generated PCs, but they expressed L-selectin only weakly. Finally, a median value of 0·4 × 10(6) /kg donor PCs - one-thirtieth of the overall PC count in a healthy adult - was grafted into patients, which could contribute to immune memory recovery.
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Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma.
Haematologica
PUBLISHED: 09-30-2010
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Proliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g. aurora kinase inhibitors) compounds.
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Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95.
Br. J. Haematol.
PUBLISHED: 08-25-2010
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Peripheral T-Cell lymphomas (PTCL) are relatively rare diseases but appear to be highly aggressive and display worse remission and survival rates than B-cell lymphomas. Despite unsatisfactory results with the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen, it remains the reference front-line therapy in these diseases, but has not been challenged in phase III trials. The Groupe Ouest Est dEtude des Leucémies et Autres Maladies du Sang (GOELAMS) devised an alternative therapeutic schedule including etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (VIP-reinforced-ABVD; VIP-rABVD) and compared it to CHOP/21 as front-line treatment in non-cutaneous PTCL. All newly diagnosed patients were eligible. The primary objective was to improve the 2-year event-free survival (EFS) rate. Secondary objectives were to compare the response rate, overall survival, and toxicities as well as identify prognostic factors. Eighty-eight patients were identified between 1996 and 2002. Both arms were well balanced for patients characteristics in terms of histological and clinical presentation. No significant difference was observed between the two arms in terms of 2-year EFS. Anaplastic large cell lymphoma type and Ann Arbor stage I-II were identified as two independent favourable prognostic factors influencing survival. VIP-rABVD was not superior to CHOP/21 in terms of EFS as first-line treatment of PTCL, confirming that CHOP/21 remains the reference regimen in these lymphomas.
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High ratio of interfollicular CD8/FOXP3-positive regulatory T cells is associated with a high FLIPI index and poor overall survival in follicular lymphoma.
Exp Ther Med
PUBLISHED: 06-25-2010
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Several studies have highlighted the importance of the microenvironment in the behaviour of follicular lymphoma (FL). We conducted an immunohistochemical analysis to assess the role of different cell subpopulations, i.e. CD8, CD68 and forkhead box protein P3 (FOXP3)-positive regulatory T cells (Treg cells) in 84 lymph nodes of 58 patients with FL (58 at diagnosis, 26 at relapse). Since the overall effect of Tregs is considered to depend on their number in relation to CD8(+) effector T cells, we determined the corresponding ratio for each patient and correlated the results with clinical parameters. The interfollicular CD8/FOXP3(+) cell ratio was significantly higher in patients with histological grade 3 tumours (2.04 vs. 1.63) and with a high risk FLIPI index (2.99 vs. 1.53) compared to those with grade 1-2 tumours or a low-intermediate FLIPI index. Similar results were obtained for the follicular CD8(+)/FOXP3(+) cell ratio. The interfollicular CD8/FOXP3 ratio was found to have prognostic value [a 5-year overall survival (OS) of 82 vs. 59% for a ratio of ±1.68]. In addition, an interfollicular FOXP3(+) cell number of more than 86 cells/mm(2) was correlated with a more favourable outcome (p=0.03). When patients at diagnosis and relapse were compared, a significant difference (p=0.05) in the localization (interfollicular vs. intrafollicular) of FOXP3(+) cells was observed. The CD8/FOXP3 ratio in the interfollicular areas was significantly different (1.66 at diagnosis vs. 2.2 at relapse, p=0.05). The presence of a small number of FOXP3(+) cells with a high CD8/FOXP3 ratio is probably the indicator of an active immune response during tumour development, with lymphoma cells acting as targets or bystanders.
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Growth factors in multiple myeloma: a comprehensive analysis of their expression in tumor cells and bone marrow environment using Affymetrix microarrays.
BMC Cancer
PUBLISHED: 05-13-2010
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Multiple myeloma (MM) is characterized by a strong dependence of the tumor cells on their microenvironment, which produces growth factors supporting survival and proliferation of myeloma cells (MMC). In the past few years, many myeloma growth factors (MGF) have been described in the literature. However, their relative importance and the nature of the cells producing MGF remain unidentified for many of them.
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[Monoclonal antibody therapy for non-Hodgkins lymphoma].
Rev Prat
PUBLISHED: 03-13-2010
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Anti-CD20 monoclonal antibodies are currently used for non-Hodgkins lymphoma treatment and Rituximab (MabThera) and ibritumomab-tiuxetan (Zevalin) currently approved for clinical use. Rituximab has improved survival of patients with follicular and diffuse large B cells lymphoma. Rituximab is safe with uncommon side effects mainly observed during the first infusion. It is basically used associated with chemotherapy every three weeks and also as maintenance therapy for relapsed follicular lymphoma. A better understand of its mechanisms of action has allowed to develop new generation of monoclonal antibody currently tested in clinical trials.
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Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma. Combined results of two prospective phase II trials from the French GOELAMS group.
Haematologica
PUBLISHED: 03-10-2010
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Background There is currently no international consensus for first-line treatment (prior to autologous stem cell transplantation) in mantle cell lymphoma patients. Here, we investigated the efficacy and tolerance of VAD associated with chlorambucil (VAD+C) and rituximab or not before autologous stem cell transplantation.
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[Therapeutic monoclonal antibodies in onco-hematology].
Med Sci (Paris)
PUBLISHED: 12-29-2009
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Rituximab, a chimeric monoclonal anti-CD20 antibody, was introduced into clinical practice in 1997, and has proven to be highly effective in the treatment of B-lymphoproliferative disorders and autoimmune diseases. Despite such success, in vivo mechanisms of action of anti-CD20 have only recently began to be unraveled, pointing to the crucial role of antibody-dependent cellular cytotoxicity response mediated through Fcg receptor signalling. Better understanding of pharmacokinetics and factors influencing individual exposure mediated through anti-CD20 will allow to engineer these molecules to increase their effector responses. Meanwhile, other formats have also been investigated, such as radiolabeled anti-CD20, or coupling of antibodies to cytotoxic drugs such as anti-CD33 used in myeloid leukemia. However these antibodies are used in combination with standard chemotherapy and cannot substitute for cytotoxic drugs. This review summarizes the knowledge acquired through our clinical use of anti-CD20 and authorized monoclonal antibodies in oncohematology and proposes some news areas that will lead to the development of new and more effective therapeutic strategies.
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Increased plasma-immune cytokines throughout the high-dose melphalan-induced lymphodepletion in patients with multiple myeloma: a window for adoptive immunotherapy.
J. Immunol.
PUBLISHED: 12-04-2009
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High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients with multiple myeloma. However, lymphocyte reconstitution is impaired after HDM. Recent work has suggested that the lymphopenia period occurring after various immunosuppressive or chemotherapy treatments may provide an interesting opportunity for adoptive antitumor immunotherapy. The objective of this study was to determine an immunotherapy window after HDM and ASCT, evaluating T cell lymphopenia, and measuring circulating immune cytokine concentrations in patients with multiple myeloma. The counts of T cell subpopulations reached a nadir at day 8 post-ASCT (day 10 post-HDM) and recovered by day 30. IL-6, IL-7, and IL-15 plasma levels increased on a median day 8 post-ASCT, respectively, 35-fold, 8-fold, and 10-fold compared with pre-HDM levels (p < or = 0.05). The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation. In conclusion, the early lymphodepletion period, occurring 4-11 d post-HDM and ASCT, is associated with an increase of circulating immune cytokines and could be an optimal window to enhance the survival and proliferation of polyclonal T cells present in the ASC autograft and also of specific antimyeloma T cells previously expanded in vitro.
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gammadelta T lymphocytes count is normal and expandable in peripheral blood of patients with follicular lymphoma, whereas it is decreased in tumor lymph nodes compared with inflammatory lymph nodes.
J. Immunol.
PUBLISHED: 11-30-2009
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gammadelta T lymphocytes are attractive effector cells for immunotherapy. In vitro, they can be expanded and kill efficiently a variety of tumor cells. The frequency and distribution of gammadelta T lymphocytes were compared in tumor lymph nodes of 51 patients with follicular lymphoma lymph nodes (FL-LNs) and 28 patients with inflammatory lymph nodes (I-LNs). gammadelta and CD8 T lymphocytes were less abundant in FL-LNs than in I-LNs (p
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Process improvement in amino acid N-carboxyanhydride synthesis by N-carbamoyl amino acid nitrosation.
Amino Acids
PUBLISHED: 04-11-2009
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Amino acid N-carboxyanhydrides (NCA), convenient monomer for polypeptide synthesis, are easily prepared in high purity as the result of N-carbamoyl amino acids (CAA) nitrosation by gaseous NOx (4:1 NO + O2 mixture, or NOCl) in toluene. Removal of polar side products is then efficiently carried out during subsequent work-up and crystallisation so that the resulting NCA obtained in good yield is suitable for controlled, primary amine-initiated polymerisation.
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Induction of angiogenesis by normal and malignant plasma cells.
Blood
PUBLISHED: 03-18-2009
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Abundant bone marrow angiogenesis is present in almost all myeloma patients requiring therapy and correlated to treatment response and survival. We assessed the expression of 402 angiogenesis-associated genes by Affymetrix DNA microarrays in 466 samples, including CD138-purified myeloma cells (MMCs) from 300 previously untreated patients, in vivo microcirculation by dynamic contrast-enhanced magnetic resonance imaging, and in vitro angiogenesis (AngioKit-assay). Normal bone marrow plasma cells (BMPCs) express a median of 39 proangiogenic (eg, VEGFA, ADM, IGF-1) and 28 antiangiogenic genes (eg, TIMP1, TIMP2). Supernatants of BMPCs unlike those of memory B cells induce angiogenesis in vitro. MMCs do not show a significantly higher median number of expressed proangiogenic (45) or antiangiogenic (31) genes, but 97% of MMC samples aberrantly express at least one of the angiogenic factors HGF, IL-15, ANG, APRIL, CTGF, or TGFA. Supernatants of MMCs and human myeloma cell lines induce significantly higher in vitro angiogenesis compared with BMPCs. In conclusion, BMPCs express a surplus of proangiogenic over antiangiogenic genes transmitting to the ability to induce in vitro angiogenesis. Aberrant expression of proangiogenic and down-regulation of antiangiogenic genes by MMCs further increases the angiogenic stimulus, together leading to bone marrow angiogenesis at various degrees in all myeloma patients.
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Expression of genes encoding for proteins involved in heparan sulphate and chondroitin sulphate chain synthesis and modification in normal and malignant plasma cells.
Br. J. Haematol.
PUBLISHED: 03-02-2009
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Syndecan-1 is a proteoglycan that concentrates heparin-binding factors on the surface of multiple myeloma cells, and probably plays a major role in multiple myeloma biology. As heparan sulphate and chondroitin sulphate are the bioactive components of syndecan-1, we analysed the signature of genes encoding 100 proteins involved in synthesis of these chains, i.e. from precursor uptake to post-translational modifications, using Affymetrix microarrays. The expression of enzymes required for heparan sulphate and chondroitin sulphate biosynthesis was shown to increase in parallel with syndecan-1 expression, throughout the differentiation of memory B cells into plasmablasts and normal bone marrow plasma cells. Sixteen genes were significantly different between normal and malignant plasma cells, nine of these genes -EXT2, CHSY3, CSGALNACT1, HS3ST2, HS2ST1, CHST11, CSGALNACT2, HPSE, SULF2 - encode proteins involved in glycosaminoglycan chain synthesis or modifications. Kaplan-Meier analysis was performed in two independent series of patients: B4GALT7, CSGALNACT1, HS2ST1 were associated with a good prognosis whereas EXT1 was linked to a bad prognosis. This study provides an overall picture of the major genes encoding for proteins involved in heparan sulphate and chondroitin sulphate synthesis and modifications that can be implicated in normal and malignant plasma cells.
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The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor.
Blood
PUBLISHED: 02-18-2009
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A plethora of myeloma growth factors (MGFs) has been identified, but their relative importance and cooperation have not been determined. We investigated 5 MGFs (interleukin-6 [IL-6], insulin-like growth factor type 1 [IGF-1], hepatocyte growth factor [HGF], HB-epidermal growth factor [HB-EGF], and a proliferation-inducing ligand [APRIL]) in serum-free cultures of human myeloma cell lines (HMCLs). In CD45(-) HMCLs, an autocrine IGF-1 loop promoted autonomous survival whereas CD45(+) HMCLs could not survive without addition of MGFs, mainly IGF-1 and IL-6. IGF-1 was the major one: its activity was abrogated by an IGF-1R inhibitor only, whereas IL-6, HGF, or HB-EGF activity was inhibited by both IGF-1R- and receptor-specific inhibition. APRIL activity was inhibited by its specific inhibitor only. Of the investigated MGFs and their receptors, only expressions of IGF-1R and IL-6R in multiple myeloma cells (MMCs) of patients delineate a group with adverse prognosis. This is mainly explained by a strong association of IGF-1R and IL-6R expression and t(4;14) translocation, but IGF-1R expression without t(4;14) can also have a poor prognosis. Thus, IGF-1-targeted therapy, eventually in combination with anti-IL-6 therapy, could be promising in a subset of patients with MMCs expressing IGF-1R.
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Carotenoid-based colours reflect the stress response in the common lizard.
PLoS ONE
PUBLISHED: 02-16-2009
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Under chronic stress, carotenoid-based colouration has often been shown to fade. However, the ecological and physiological mechanisms that govern colouration still remain largely unknown. Colour changes may be directly induced by the stressor (for example through reduced carotenoid intake) or due to the activation of the physiological stress response (PSR, e.g. due to increased blood corticosterone concentrations). Here, we tested whether blood corticosterone concentration affected carotenoid-based colouration, and whether a trade-off between colouration and PSR existed. Using the common lizard (Lacerta vivipara), we correlatively and experimentally showed that elevated blood corticosterone levels are associated with increased redness of the lizards belly. In this study, the effects of corticosterone did not depend on carotenoid ingestion, indicating the absence of a trade-off between colouration and PSR for carotenoids. While carotenoid ingestion increased blood carotenoid concentration, colouration was not modified. This suggests that carotenoid-based colouration of common lizards is not severely limited by dietary carotenoid intake. Together with earlier studies, these findings suggest that the common lizards carotenoid-based colouration may be a composite trait, consisting of fixed (e.g. genetic) and environmentally elements, the latter reflecting the lizards PSR.
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Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma.
Blood
PUBLISHED: 01-26-2009
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Genetic instability and cellular proliferation have been associated with aurora kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of aurora-A, -B, and -C was determined by Affymetrix DNA microarrays in 784 samples including 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.
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Gene expression of anti- and pro-apoptotic proteins in malignant and normal plasma cells.
Br. J. Haematol.
PUBLISHED: 01-08-2009
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The survival of malignant plasma cells is a key event in disease occurrence, progression and chemoresistance. Using DNA-microarrays, we analysed the expression of genes coding for 58 proteins linked with extrinsic and intrinsic apoptotic pathways, caspases and inhibitor of apoptosis proteins. We considered six memory B cells (MBC), seven plasmablasts (PPC), seven bone marrow plasma cells (BMPC) and purified myeloma cells (MMC) from 92 newly-diagnosed patients. Forty out of the 58 probe sets enabled the separation of MBC, PPC and BMPC in three homogeneous clusters, characterized by an elevated expression of TNFRSF10A, TNFRSF10B, BCL2A1, CASP8, CASP9 and PMAIP1 genes for MBC, of FAS, FADD, AIFM1, BIRC5, CASP CASP2, CASP3 and CASP6 for PPC and of BCL2, MCL1, BID, BIRC3 and XIAP for BMPC. Thus, B cell differentiation was associated with change of expression of pro-apoptotic and anti-apoptotic genes. Regarding MMC, the major finding was TRAIL upregulation that might be counteracted by a high osteoprotegerin production by BM stromal cells and a decreased expression of FAS, APAF1 and BNIP3 compared to normal BMPC. Out of the 40 genes, CASP2 and BIRC5 expression in MMC had adverse prognosis in two independent series of previously-untreated patients.
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Residual malignant and normal plasma cells shortly after high dose melphalan and stem cell transplantation. Highlight of a putative therapeutic window in Multiple Myeloma?
Oncotarget
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Multiple Myeloma (MM) is an incurable malignant plasma cell disorder. We have evaluated the counts of Multiple Myeloma Cells (MMCs) and normal plasma cells (N-PCs), seven days after high-dose melphalan (HDM) and autologous stem transplantation (ASCT). Two third of patients had detectable minimal residual disease (MRD+) (71.7 MMCs/µL) after induction treatment with dexamethasone and proteasome inhibitor. MMC counts were reduced by 92% (P ? .05) but not eradicated 7 days after HDM+ASCT. Post-HDM+ASCT MMCs were viable and bathed in a burst of MMC growth factors, linked with post-HDM aplasia. In one third of patients (MRD- patients), MMCs were not detectable after induction treatment and remained undetectable after HDM+ASCT. Major difference between MRD- and MRD+ patients is that N-PC counts were increased 3 fold (P?.05) by HDM+ASCT in MRD- patients, but were unaffected in MRD+ patients. Possible explanation could be that clearance of MMCs in MRD- patients makes more niches available for N-PCs. Thus, MMCs are not fully eradicated shortly after HDM, are bathed in high concentrations of MMC growth factors in an almost desert BM, are viable in short-term culture, which suggests providing additional therapies shortly after HDM to kill resistant MMCs before full repair of lesions.
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Where do adaptive shifts occur during invasion? A multidisciplinary approach to unravelling cold adaptation in a tropical ant species invading the Mediterranean area.
Ecol. Lett.
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Evolution may improve the invasiveness of populations, but it often remains unclear whether key adaptation events occur after introduction into the recipient habitat (i.e. post-introduction adaptation scenario), or before introduction within the native range (i.e. prior-adaptation scenario) or at a primary site of invasion (i.e. bridgehead scenario). We used a multidisciplinary approach to determine which of these three scenarios underlies the invasion of the tropical ant Wasmannia auropunctata in a Mediterranean region (i.e. Israel). Species distribution models (SDM), phylogeographical analyses at a broad geographical scale and laboratory experiments on appropriate native and invasive populations indicated that Israeli populations followed an invasion scenario in which adaptation to cold occurred at the southern limit of the native range before dispersal to Israel. We discuss the usefulness of combining SDM, genetic and experimental approaches for unambiguous determination of eco-evolutionary invasion scenarios.
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Identification of pluripotent and adult stem cell genes unrelated to cell cycle and associated with poor prognosis in multiple myeloma.
PLoS ONE
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Gene expression-based scores used to predict risk in cancer frequently include genes coding for DNA replication, repair or recombination. Using two independent cohorts of 206 and 345 previously-untreated patients with Multiple Myeloma (MM), we identified 50 cell cycle-unrelated genes overexpressed in multiple myeloma cells (MMCs) compared to normal human proliferating plasmablasts and non-proliferating bone marrow plasma cells and which have prognostic value for overall survival. Thirty-seven of these 50 myeloma genes (74%) were enriched in genes overexpressed in one of 3 normal human stem cell populations--pluripotent (18), hematopoietic (10) or mesenchymal stem cells (9)--and only three genes were enriched in one of 5 populations of differentiated cells (memory B lymphocytes, T lymphocytes, polymorphonuclear cells, monocytes, osteoclasts). These 37 genes shared by MMCs and adult or pluripotent stem cells were used to build a stem cell score ((SC)score), which proved to be strongly prognostic in the 2 independent cohorts of patients compared to other gene expression-based risk scores or usual clinical scores using multivariate Cox analysis. This finding highlights cell cycle-unrelated prognostic genes shared by myeloma cells and normal stem cells, whose products might be important for normal and malignant stem cell biology.
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The NF-?B member p65 controls glutamine metabolism through miR-23a.
Int. J. Biochem. Cell Biol.
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Cancer cells have elevated aerobic glycolysis that is termed the Warburg effect. But several tumor cells, including leukemic cells, also increase glutamine metabolism, which is initiated by glutaminase (GLS). The microRNA (miRNA) miR-23 targets GLS mRNA and inhibits expression of GLS protein. Here we show that in human leukemic Jurkat cells the NF-?B p65 subunit binds to miR-23a promoter and inhibits miR-23a expression. Histone deacetylase (HDAC) inhibitors release p65-induced inhibition. Jurkat cells growing in glutamine decrease proliferation due to cell accumulation in G0/G1 phase. Nevertheless, cells get used to this new source of energy by increasing GLS expression, which correlates with an increase in p65 expression and its translocation to the nucleus, leading to a higher basal NF-?B activity. Jurkat cells overexpressing p65 show increase basal GLS expression and proliferate faster than control cells in glutamine medium. Overexpressing miR-23a in leukemic cells impaired glutamine use and induces mitochondrial dysfunction leading to cell death. Therefore, p65 activation decreases miR-23a expression, which facilitates glutamine consumption allowing leukemic cells to use this alternative source of carbon and favoring their adaptation to the metabolic environment.
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Rituximab before splenectomy in adults with primary idiopathic thrombocytopenic purpura: a meta-analysis.
Br. J. Haematol.
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Primary immune thrombocytopenia (ITP) is an acquired immune-mediated disorder with absence of any underlying cause. Corticosteroids are the standard initial treatment. Splenectomy is the main second-line treatment. A trend to delay or avoid splenectomy has developed thanks to new agents like rituximab. Few studies have assessed the response rate to rituximab in chronic ITP. We performed the first meta-analysis of randomized clinical trials and observational studies on rituximab as an effective splenectomy-avoiding option in adult chronic ITP. Overall methods were adapted from published guidelines for meta-analysis (meta-analysis of observational studies in epidemiology and preferred reporting items for systematic reviews and meta-analyses). Two haematologist investigators carried out study selection and data extraction independently, recording overall response rate (ORR) and complete response (CR) as primary assessment criteria. Of 364 records were identified through electronic databases. Of 19 retrospective or prospective observational studies were retained after removing duplicate studies and full-text analyses. The ORR was 57% (95% confidence interval [CI]: 48-65), for 368 non-splenectomized patients after rituximab; CR was 41% (95% CI: 0·33-0·51) for 346 patients. Results were stable for ORR and CR in all sub-analyses. In univariate or multivariate mixed-effect meta-regression, age was the most relevant effect. According to our results, rituximab should be used in earlier in non-splenectomized patients.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.