A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis

Canonical Wnt signaling is critically involved in normal hematopoietic development and the self-renewal process of hematopoietic stem cells (HSCs). Deregulation of this pathway has been linked to a large variety of cancers, including different subtypes of leukemia. Lef-1 is a major transcription factor of this pathway and plays a pivotal role in lymphoid differentiation as well as in granulopoiesis. Here, we demonstrate Lef-1 expression in murine HSCs as well as its expression in human leukemia. Mice transplanted with bone marrow retrovirally transduced to express Lef-1 or a constitutive active Lef-1 mutant showed a severe disturbance of normal hematopoietic differentiation and finally developed B lymphoblastic and acute myeloid leukemia (AML). Lef-1–induced AMLs were characterized by immunoglobulin (Ig) DH-JH rearrangements and a promiscuous expression of lymphoid and myeloid regulatory factors. Furthermore, single cell experiments and limiting dilution transplantation assays demonstrated that Lef-1–induced AML was propagated by a leukemic stem cell with lymphoid characteristics displaying Ig DH-JH rearrangements and a B220+ myeloid marker− immunophenotype. These data indicate a thus far unknown role of Lef-1 in the biology of acute leukemia, pointing to the necessity of balanced Lef-1 expression for an ordered hematopoietic development

An individual based computational model of intestinal crypt fission and its application to predicting unrestrictive growth of the intestinal epithelium.

Intestinal crypt fission is a homeostatic phenomenon, observable in healthy adult mucosa, but which also plays a pathological role as the main mode of growth of some intestinal polyps. Building on our previous individual based model for the small intestinal crypt and on in vitro cultured intestinal organoids, we here model crypt fission as a budding process based on fluid mechanics at the individual cell level and extrapolated predictions for growth of the intestinal epithelium. Budding was always observed in regions of organoids with abundant Paneth cells. Our data support a model in which buds are biomechanically initiated by single stem cells surrounded by Paneth cells which exhibit greater resistance to viscoelastic deformation, a hypothesis supported by atomic force measurements of single cells. Time intervals between consecutive budding events, as simulated by the model and observed in vitro, were 2.84 and 2.62 days, respectively. Predicted cell dynamics was unaffected within the original crypt which retained its full capability of providing cells to the epithelium throughout fission. Mitotic pressure in simulated primary crypts forced upward migration of buds, which simultaneously grew into new protruding crypts at a rate equal to 1.03 days-1 in simulations and 0.99 days-1 in cultured organoids. Simulated crypts reached their final size in 4.6 days, and required 40 6.2 days to migrate to the top of the primary crypt. The growth of the secondary crypt is independent of its migration along the original crypt. Assuming unrestricted crypt fission and multiple budding events, a maximal growth rate of the intestinal epithelium of 0.10 days-1 43 is predicted and thus approximately 22 days are required for a 10-fold increase of polyp size. These predictions are in agreement with the time reported to develop macroscopic adenomas in mice after loss of Apc in intestinal stem cells

Eddy diffusivities for the convective boundary layer derived from LES spectral data

AbstractLarge Eddy Simulation (LES) spectral data and Taylor statistical diffusion theory are used to obtain Eddy diffusivities in a convective boundary layer. The derivation employs a fitting expression obtained from LES data for the vertical peak frequency. The vertical Eddy diffusivities are well behaved and show similar patterns and magnitudes as those derived from experimental spectral peak frequency data. In addition, this new vertical Eddy diffusivity was introduced into an advection diffusion equation which was solved by Generalized Integral Laplace Transform Technique (GILLT) method and validated with observed contaminant concentration data of the Copenhagen experiment. The results of this new approach are shown to agree with the measurements of Copenhagen

Mathematical and Statistical Techniques for Systems Medicine: The Wnt Signaling Pathway as a Case Study

The last decade has seen an explosion in models that describe phenomena in systems medicine. Such models are especially useful for studying signaling pathways, such as the Wnt pathway. In this chapter we use the Wnt pathway to showcase current mathematical and statistical techniques that enable modelers to gain insight into (models of) gene regulation, and generate testable predictions. We introduce a range of modeling frameworks, but focus on ordinary differential equation (ODE) models since they remain the most widely used approach in systems biology and medicine and continue to offer great potential. We present methods for the analysis of a single model, comprising applications of standard dynamical systems approaches such as nondimensionalization, steady state, asymptotic and sensitivity analysis, and more recent statistical and algebraic approaches to compare models with data. We present parameter estimation and model comparison techniques, focusing on Bayesian analysis and coplanarity via algebraic geometry. Our intention is that this (non exhaustive) review may serve as a useful starting point for the analysis of models in systems medicine.Comment: Submitted to 'Systems Medicine' as a book chapte

The value of position-specific priors in motif discovery using MEME

<p>Abstract</p> <p>Background</p> <p>Position-specific priors have been shown to be a flexible and elegant way to extend the power of Gibbs sampler-based motif discovery algorithms. Information of many types–including sequence conservation, nucleosome positioning, and negative examples–can be converted into a prior over the location of motif sites, which then guides the sequence motif discovery algorithm. This approach has been shown to confer many of the benefits of conservation-based and discriminative motif discovery approaches on Gibbs sampler-based motif discovery methods, but has not previously been studied with methods based on expectation maximization (EM).</p> <p>Results</p> <p>We extend the popular EM-based MEME algorithm to utilize position-specific priors and demonstrate their effectiveness for discovering transcription factor (TF) motifs in yeast and mouse DNA sequences. Utilizing a discriminative, conservation-based prior dramatically improves MEME's ability to discover motifs in 156 yeast TF ChIP-chip datasets, more than doubling the number of datasets where it finds the correct motif. On these datasets, MEME using the prior has a higher success rate than eight other conservation-based motif discovery approaches. We also show that the same type of prior improves the accuracy of motifs discovered by MEME in mouse TF ChIP-seq data, and that the motifs tend to be of slightly higher quality those found by a Gibbs sampling algorithm using the same prior.</p> <p>Conclusions</p> <p>We conclude that using position-specific priors can substantially increase the power of EM-based motif discovery algorithms such as MEME algorithm.</p

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

Treatment of limited stage follicular lymphoma with Rituximab immunotherapy and involved field radiotherapy in a prospective multicenter Phase II trial-MIR trial

<p>Abstract</p> <p>Background</p> <p>The optimal treatment of early stage follicular Lymphoma is a matter of debate. Radiation therapy has frequently been applied with a curative approach beside watchful waiting. Involved field, extended field and total nodal radiation techniques are used in various protocols, but the optimal radiation field still has to be defined. Follicular lymphoma is characterized by stable expression of the CD20 antigen on the tumour cells surface. The anti CD20 antibody Rituximab (Mabthera^®) has shown to be effective in systemic therapy of FL in primary treatment, relapse and maintenance therapy.</p> <p>Methods/design</p> <p>The MIR (Mabthera^®and Involved field Radiation) study is a prospective multicenter trial combining systemic treatment with the anti CD20 antibody Rituximab (Mabthera^®) in combination with involved field radiotherapy (30 - 40 Gy). This trial aims at testing the combination's efficacy and safety with an accrual of 85 patients.</p> <p>Primary endpoint of the study is progression free survival. Secondary endpoints are response rate to Rituximab, complete remission rate at week 18, relapse rate, relapse pattern, relapse free survival, overall survival, toxicity and quality of life.</p> <p>Discussion</p> <p>The trial evaluates the efficacy of Rituximab to prevent out-filed recurrences in early stage nodal follicular lymphoma and the safety of the combination of Rituximab and involved field radiotherapy. It also might show additional risk factors for a later recurrence (e.g. remission state after Rituximab only).</p> <p>Trial Registration</p> <p>ClinicalTrials (NCT): <a href="http://www.clinicaltrials.gov/ct2/show/NCT00509184">NCT00509184</a></p

Differential Effects of HOXB4 on Nonhuman Primate Short- and Long-Term Repopulating Cells

BACKGROUND: Hematopoietic stem cells (HSCs) or repopulating cells are able to self-renew and differentiate into cells of all hematopoietic lineages, and they can be enriched using the CD34 cell surface marker. Because of this unique property, HSCs have been used for HSC transplantation and gene therapy applications. However, the inability to expand HSCs has been a significant limitation for clinical applications. Here we examine, in a clinically relevant nonhuman primate model, the ability of HOXB4 to expand HSCs to potentially overcome this limitation. METHODS AND FINDINGS: Using a competitive repopulation assay, we directly compared in six animals engraftment of HOXB4GFP (HOXB4 green fluorescent protein) and control (yellow fluorescent protein [YFP])–transduced and expanded CD34 (+) cells. In three animals, cells were infused after a 3-d transduction culture, while in three other animals cells were infused after an additional 6–9 d of ex vivo expansion. We demonstrate that HOXB4 overexpression resulted in superior engraftment in all animals. The most dramatic effect of HOXB4 was observed early after transplantation, resulting in an up to 56-fold higher engraftment compared to the control cells. At 6 mo after transplantation, the proportion of marker gene–expressing cells in peripheral blood was still up to 5-fold higher for HOXB4GFP compared to YFP-transduced cells. CONCLUSIONS: These data demonstrate that HOXB4 overexpression in CD34 (+) cells has a dramatic effect on expansion and engraftment of short-term repopulating cells and a significant, but less pronounced, effect on long-term repopulating cells. These data should have important implications for the expansion and transplantation of HSCs, in particular for cord blood transplantations where often only suboptimal numbers of HSCs are available

Active and passive-source seismic imaging for exploration of deep-seated massive sulphide mineralization in the Zinkgruvan mine, south-central Sweden

[EN]This communication presents the acquisition of active and passive source seismic data in the Zinkgruvan mine in Sweden in an effort to develop highly resolved and cost-effective exploration method

Managing hematological cancer patients during the COVID-19 pandemic:an ESMO-EHA Interdisciplinary Expert Consensus

Background: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. Methods: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. Results and conclusion: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic.</p