1,721,157 research outputs found
Genomic profiling of B cell lymphoma RL cell line treated with enzastaurin
No full textBackground: Bone marrow mesenchymal stem cells support proliferation and differentiation of hematopoietic progenitor cells in vitro. Since these cells constitute a rare subset of bone marrow cells, mesenchymal stem cell preparations for clinical purposes require a preparative step of ex vivo multiplication. The aim of our study was to analyze the influence of culture duration on mesenchymal stem cell supportive activity. Design and Methods: Mesenchymal stem cells were expanded for up to ten passages. These cells and CD34+ cells were seeded in cytokine-free co-cultures after which the phenotype, clonogenic capacity and in vivo repopulating activity of harvested hematopoietic cells were assessed. Results: Early passage mesenchymal stem cells supported hematopoietic progenitor cell expansion and differentiation toward both B lymphoid and myeloid lineages. Late passage mesenchymal stem cells did not support hematopoietic progenitor cell and myeloid cell outgrowth but maintained B-cell supportive ability. In vitro maintenance of NOD/SCID mouse repopulating cells cultured for 1 week in contact with mesenchymal stem cells was effective until the fourth passage of the mesenchymal cells and declined thereafter. The levels of engraftment of CD34 + cells in NOD/SCID mice was higher when these cells were co-injected with early passage mesenchymal stem cells; however mesenchymal cells expanded beyond nine passages were ineffective in promoting CD34 + cell engraftment. Non-contact cultures indicated that mesenchymal stem cell supportive activity involved diffusible factors. Among these, interleukins 6 and 8 contributed to the supportive activity of early passage mesenchymal stem cells but not to those of late passage cells. The phenotype, as well as fat, bone and cartilage differentiation capacity, of mesenchymal stem cells did not change during their culture. Conclusions: Extended culture of mesenchymal stem cells alters the ability of these cells to support hematopoietic progenitor cells without causing concomitant changes in their phenotype or differentiation capacity
Sphingosine kinase 1 as a potential target to inhibit proliferation of myeloid leukemia cells
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Primary plasma cell leukemia: identity card 2016
No full textPrimary plasma cell leukemia (PPCL) is an aggressive and rare variant of multiple myeloma (MM), characterized by peculiar adverse clinical and biological features. Though the poor outcome of PPCL has been slightly improved by novel treatments during the last 10 years, due to the limited number of available studies in this uncommon disease, optimal therapy remains a classic unmet clinical need. Anyway, in the real-life practice, induction with a bortezomib-based three-drug combination, including dexamethasone and, possibly, lenalidomide, or, alternatively, thalidomide, cyclophosphamide, or doxorubicin, is a reasonable first-line option. This approach may be particularly advisable for patients with adverse cytogenetics, hyperleucocytosis, and rapidly progressive disease, in whom a fast response is required, or for those with suboptimal renal function, where, however, lenalidomide should be used with caution until renal activity is restored. In younger subjects, leukemia/lymphoma-like more intensive regimens, including hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone or continue-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide, may be also combined with bortezomib +/- thalidomide. Treatment must be started immediately after a diagnosis of PPCL is made to avoid the risk of irreversible disease complications and, in such a context, the prevention of tumor lysis syndrome is mandatory. In patients eligible for autologous stem cell transplantation (AuSCT), other alkylating agents, in particular melphalan, should be initially avoided in order to allow adequate collections of CD34+ peripheral blood stem cells (PBSC). A combination of lenalidomide and dexamethasone may be a valuable alternative option to manage older or unfit patients or those with slower disease evolution or with signs of neuropathy, contraindicating the use of bortezomib. Patients not suitable for transplant procedures should continue the treatment, if a response occurs and if tolerated, considering the possibility of a prolonged maintenance therapy. AuSCT should be pursued in all eligible patients less than 65 years old who achieve a significant response after a short course of induction treatment. PBSC collection should reach a threshold of at least 5 × 10(6) CD34+ PBSC/kg using cyclophosphamide plus G-CSF and adding the mobilizing agent plerixafor, if necessary. High-dose melphalan (HDM) (200 or 140 mg/m(2), according to age and renal function) remains the preferable conditioning regimen. A second AuSCT should be always considered, even in patients achieving complete response (CR) after the first AuSCT, as the short progression-free survival (PFS) generally seen in PPCL suggests the persistence of a relevant burden of residual disease; this provides a strong rationale for the use of post-transplantation therapies in PPCL to improve depth of response, to maintain remission, and, possibly, to increase survival, though consolidation and/or maintenance strategies with novel agents, whose efficacy has been well demonstrated in MM, have not been still extensively evaluated in PPCL. The search of a suitable donor should start as soon as possible and an allogeneic stem cell transplant (AlloSCT) with a myeloablative conditioning (MAC) regimen discussed with younger patients responsive to induction therapy and with poor prognostic parameters at diagnosis. A sequence of AuSCT followed by reduced intensity conditioning (RIC) or non-myeloablative (NMA) AlloSCT may be considered in selected cases. Salvage therapies for relapsed/refractory disease, especially using new drugs not employed at diagnosis, are sometimes effective in the short term, but a rapid relapse is still generally the rule; AlloSCT in relapsed and eligible patients with sensitive disease after salvage treatments is, therefore, recommended
In silico characterization of miRNA and long non-coding RNA interplay in multiple myeloma
Full text linkThe identification of deregulated microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in multiple myeloma (MM) has progressively added a further level of complexity to MM biology. In addition, the cross-regulation between lncRNAs and miRNAs has begun to emerge, and theoretical and experimental studies have demonstrated the competing endogenous RNA (ceRNA) activity of lncRNAs as natural miRNA decoys in pathophysiological conditions, including cancer. Currently, information concerning lncRNA and miRNA interplay in MM is virtually absent. Herein, we investigated in silico the lncRNA and miRNA relationship in a representative datasets encompassing 95 MM and 30 plasma cell leukemia patients at diagnosis and in four normal controls, whose expression profiles were generated by a custom annotation pipeline to detect specific lncRNAs. We applied target prediction analysis based on miRanda and RNA22 algorithms to 235 lncRNAs and 459 miRNAs selected with a potential pivotal role in the pathology of MM. Among pairs that showed a significant correlation between lncRNA and miRNA expression levels, we identified 11 lncRNA-miRNA relationships suggestive of a novel ceRNA network with relevance in MM
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
The notch ligands Jagged1 and 2 are a potential therapeutic target in multiple myeloma- associated bone disease
No full textBackground: Bone disease is still a relevant issue in multiple myeloma (MM), since it not only affects patients quality of
life but it also promote tumor growth and survival, finally contributing to the fatal outcome of this disease. The Notch
oncogenic pathway is dysregulated in MM, due to the hyperexpression of the Jagged 1 and 2 ligands. This alteration
improve the ability of MM cells to establish pathological interactions with the bone marrow (BM) niche, finally promoting
tumor progression.
Notch is also a key regulator of bone tissue remodeling and skeletal development.
Aims: The aim of this work was to provide a rationale for the targeting of the two Notch ligands Jagged 1 and 2 in MM-
driven bone disease. To address this issue we assessed:
•
The role of the Notch pathway in MM-associated osteoclastogenesis
•
The effects of Jagged1/2 silencing on the ability of MM cells to activate the Notch pathway in OCLs and boost bone
resorption
Methods: OCL differentiation of Raw264.7 cells was induced by treating them with 50ng/ml mRANKL or co-culturing with
MM cells or their conditioned medium (CM). After 5-7days cells were stained using the TRAP Kit and counted. DAPT was
used at a concentration of 50μM. Select RNAi
TM
siRNA system (Invitrogen) was used according to the manufacturer’s
guidelines for the selective knock-down of Jag1 and Jag2. Jagged1 recombinant peptide was used at 0.5μg/ml. anti-
RANKL neutralizing antibody was used at 0.1μg/ml.Total RNA was isolated using TRI-Reagent. cDNA was prepared
through MMLV reverse transcriptase, then quantitative PCR (qPCR) was performed by Maxima SYBR Green qPCR
Master Mix.RANKL was quantify by ELISA Assay and flow cytometry.
Results: Our findings indicate that the autonomous release of RANKL (Receptor activator of nuclear factor kappa-B
ligand) by MM cells is essential for their ability to boost osteoclastogenesis. Interestingly, RANKL release is Notch-
dependent, since Jagged1/2 silencing in MM cells causes the inhibition of the Notch pathway and impairs their ability to
secrete RANKL and to stimulate osteoclasts (OCLs) differentiation and activity.
MM-derived Jagged are also able to directly activate the pro-osteoclastogenic Notch signaling in neighboring pre-OCLs,
boosting their differentiation.
Moreover, Jagged1/2 are essential for the interaction of MM cells with BM stromal cells (BMSCs), that can further
enhance the osteoclastogenic potential of tumor cells.
Jagged1/2 withdrawal blocks the cross-talk between MM cells and the surrounding BMSCs and pre-OCLs, finally causing
a decrease in the formation of mature OCLs and in bone resorption.
Summary/Conclusion: Our study provided the first evidence that two Notch ligands dysregulated in MM, Jagged 1 and
2, play an essential role in myeloma-induced osteoclast differentiation and bone resorption activity. Jagged ligands can
trigger Notch signaling in the same MM cells, resulting in the release of the key osteoclastogenic factor RANKL, and may
also activate Notch signaling in the neighboring osteoclast progenitor further promoting their differentiation. Finally, we
demonstrated that MM cells are able to crosstalk with BMSCs which are able to stimulate low-RANKL expressing
myeloma cells, to release higher amount of RANKL and acquire osteoclastogenic ability. Importantly, BMSC support can
be prevented by silencing Jagged ligands on myeloma cells. All together, our results demonstrate that the two Notch
ligands Jagged1 and 2 represents two new promising therapeutic targets in MM-associated bone disease
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