mantle cell lymphoma

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Identification of B cell antigen receptor epitopes of mantle cell lymphoma B cells

Identification of B cell antigen receptor epitopes of mantle cell lymphoma B cells

The B cell receptor is a functional key molecule of B cells. Since it is also expressed in most and functional in many B cell neoplasias (1.3.2), it is likely that that the BCR is salient to lymphoma cell survival at least at some point of lymphomagenesis and disease progression. In fact, the blockage of this pathway showed promising therapeutic effects, partially beyond any therapeutic strength observed before, in chronic lymphocytic leukaemia and mantle cell lymphoma 164–166,203–205 . Nevertheless, the role of the BCR in lymphoma is not completely understood and it is unknown which antigens are bound and potentially stimulate tumour cell growth in individual patient cases. Analysis of the BCR Ig repertoire can give valuable information about the developmental stage of the B cell at the supposed time of malignant transformation. Despite the fact that MCL is a rare disease, it was possible to acquire 32 MCL samples for this study. The crucial step for all downstream experiments was the identification of the Ig sequence of the malignant B cells (4.1.1). It was possible to determine the variable heavy chain Ig sequence of 24 out of 32 investigated samples. Moreover, for all but two samples the associated Ig light chain was determined, as well. In these two cases, multiple light chain sequences were identified for the κ- and λ-isotype. Since no unequivocal monoclonal sequence was found, the light chains of these patients were regarded as polyclonal. This observation raised the possibility that malignant transformation of a clone occurred before the rearrangement of the light chain, i.e. before the transition from pre-B to B cell. However, whether the observed polyclonality was a technical artefact or a special property of these two patient samples remained elusive.
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Radiomic features of glucose metabolism enable prediction of outcome in mantle cell lymphoma

Radiomic features of glucose metabolism enable prediction of outcome in mantle cell lymphoma

Mantle cell lymphoma (MCL) is a rare subtype of B cell non- Hodgkin lymphoma, and can be associated with an aggressive or, less frequently, an indolent course [ 1 ]. Despite the avail- ability of novel types of treatment, the prognosis in MCL patients is generally considered to be poor [ 2 ], with 5-year survival rates as low as 50% [ 1 ]. For estimation of prognosis, adapted versions of the International Prognostic Score (IPI) – the so-called MIPI scores, which incorporate age, ECOG per- formance status, leucocyte count, lactic dehydrogenase levels and in some variants also the Ki-67 proliferation index – are used in clinical practice [ 1 ]. These MIPI scores were built upon data for, and used for prediction of, 5-year survival, with This article is part of the Topical Collection on Advanced Image Analyses
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Regulation of the BH3-only protein NOXA in mantle cell lymphoma : relevance for novel treatment concepts

Regulation of the BH3-only protein NOXA in mantle cell lymphoma : relevance for novel treatment concepts

Orlistat is the second substance found in the present study to induce the BH3-only protein NOXA in MCL cells (Figure 15). Orlistat is an inhibitor of the fatty acid synthase (FASN). The metabolic enzyme is catalyzing the synthesis of the fatty acid palmitate and is a key player in de novo lipogenesis, an important metabolic pathway that has been linked to the pathogenesis of several types of tumors (Kuhajda, 2006; Menendez and Lupu, 2007). Gelebart et al. recently showed overexpression of FASN and efficacy of Orlistat in MCL cell lines and primary MCL cells (Gelebart et al., 2012). However, the underlying mechanisms of the cytotoxic effects of Orlistat in MCL remained unclear. Induction of cell cycle arrest and apoptosis via the extrinsic pathway as well as intrinsic pathway has been shown in response to Orlistat treatment in different tumor models (Kant et al., 2012; Knowles et al., 2004, 2008). In the present work, NOXA was determined as the key mediator of Orlistat-induced cell death in MCL cells (Figure 17). Intriguingly, Orlistat-mediated FASN inhibition stabilized NOXA by impairing ubiquitination of the pro-apoptotic protein (Figure 22 and Figure 23). An existing crosstalk between fatty acid metabolism and the UPS has been proposed by several reports (Little et al., 2008). FASN protein stability, for example, is regulated by the de-ubiquitinating enzyme USP2A (Graner et al., 2004). On the other hand, FASN appears to regulate expression of multiple enzymes involved in protein ubiquitination including E2 ubiquitin conjugating enzymes and E3 ubiquitin ligases (Knowles and Smith, 2007b). Interestingly, FASN inhibition by Orlistat was demonstrated to reduce expression of Skp2, a component of an CRL E3 ligase (Knowles et al., 2004). Therefore, Orlistat might indirectly target the ubiquitin ligase of NOXA by mediating its down-regulation through inhibition of fatty acid metabolism.
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The influence of deregulated CD30 signaling and gamma-herpesviral infection on the development of B cell lymphoma

The influence of deregulated CD30 signaling and gamma-herpesviral infection on the development of B cell lymphoma

tion. Other translocations are by-products of SHM because they are present within or nearby of somatically mutated rearranged V(D)J- genes. During class switch recombi- nation, DNA breaks are introduced in the IgH constant switch regions. These break- points characterize the third type of translocations. Examples for IgH translocations are BCL2 found in the FL, MYC in the BL and cyclin D1 in the mantle cell lymphoma [Chesi, 1996, Johnson et al., 2009, Gostissa et al., 2009]. During SHM, mutations are in- troduced in the immunoglobulin variable regions of the BCR through substitution, dele- tion, or insertions of single base pairs. In lymphomas, aberrant SHM leads to mutations in genes in addition to the V genes. For example, the DLBCL displays mutations in proto- oncogenes like PIM1, MYC, RhoH/TTF, and PAX5 [Pasqualucci et al., 2001]. The char- acteristic mutation pattern in these genes is similar to SHM in the V-gene region. However, normal GC B cells do not display mutations in these loci [Pasqualucci et al., 2001]. One of the most common targets influenced by translocation, amplification, and muta- tion occurring in the lymphomas are genes encoding for TFs. BCL6, IRF4 and BLIMP-1 which are important TFs during the GC reaction belong to the main targets in this pro- cess. Therefore, the following section explains several mutations in these TFs leading to lymphoma development (see: 3.1.3). The master regulator of the GC reaction, BCL6 is often deregulated in B cell lymphomas. For example, in DLBCL and FL, the promoter re- gion of BCL6 is replaced by constitutive active heterologous regulatory regions leading to an impaired downregulation of BCL6 in these lymphomas [Ye et al., 1993]. This in turn leads to a block in PC differentiation, increased proliferation, and a block of the DNA repair mechanisms [Shaffer et al., 2000, Phan et al., 2005]. Multiple myeloma and ABC DLBCL reveal a high expression of IRF4 [Alizadeh et al., 2000]. The active NFκB path- way in these lymphomas mediates directly the expression of IRF4 which plays a key role in PC differentiation by transactivating PRDM1 and repressing BCL6 [Saito et al., 2007]. The difference between multiple myeloma and the ABC DLBCL is the differentiation stage of the lymphoma cells. The cells of multiple myeloma have a PC phenotype dis- playing the full gene expression profile of mature PC, the cells of the ABC DLBCL have a plasmablastic phenotype caused by the inactivation of PRDM1 [Pasqualucci et al., 2006].
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Coupling thermodynamic mineralogical models and mantle convection

Coupling thermodynamic mineralogical models and mantle convection

chemical models of the mantle and reasonable mantle temperatures. In this system I have performed a system Gibbs free energy minimization, including pure end-member phases and a non-ideal formulation for solid solutions. Solid solutions were subdivided into discrete pseudocompounds and treated as stoichiometric phases during computation of chemical equilibrium by the simplex method. I have complemented the thermodynamic model with a model of shear wave properties [Stixrude and Lithgow-Bertelloni, 2005] to obtain a full description of aggregate elastic properties (density, bulk and shear moduli) that provide a useful basis for the consideration of seismic and geodynamic models of the Earth’s mantle. By using this new thermodynamic database for the mantle I have coupled the resulting density dynamically (through the buoyancy term) with mantle convection models. I have linked the database with a high-resolution 2-D convection code (2DTERRA), dynamically coupling the thermodynamic model (density) with the conservation equations of mantle flow. The coupled model is run for different parameterisations of viscosity, initial tem- perature conditions, and varying internal vs. external heating. A common feature of all the models is that the convecting flow creates a characteristic discontinuity of temperature around 660 km depth in order to compensate for the entropy change due to the phase transitions. I have studied the importance and the possible consequences of such a thermal regime on the excess temperature of plumes and on the transition zone thickness. The thermodynamic mantle mineralogy model provides the conversion of the temperature field into seismic velocities so that predictions from mantle convection can be compared to seis- mic observations in terms of radial profiles or lateral variations. This approach allows us to predict a number of seismic observables from the convection model, all of which agree remarkably well with observations from seismic tomography.
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Ba, Rb and Cs in the Earth's Mantle 

Ba, Rb and Cs in the Earth's Mantle 

In conjunction with the "standard" assumption that the relative abundances of refractory elements are chondritic, so that the absolute terrestrial Ba and Sr abundances are kn[r]

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Frequency and relevance of genetic alterations of the ID3-TCF3-CCND3 pathway in pediatric mature B-cell Non-Hodgkin lymphoma

Frequency and relevance of genetic alterations of the ID3-TCF3-CCND3 pathway in pediatric mature B-cell Non-Hodgkin lymphoma

2) Inclusion criteria of samples / diagnostic quality: The inclusion criteria for evaluation in the validation cohorts varied in between the presented studies (see above) and information on diagnostic quality was limited especially in the studies of Schmitz and Love. Attempts to determine the frequency of ID3 mutations in BL are further complicated by the diagnostic difficulty of BL. Despite enormous efforts to standardize histopathological differentiation of BL and DLBCL, this distinction is still vulnerable. Therefore careful histopathological review and description of the evaluated cases is necessary to allow the comparison of identified ID3 mutations rates. This is of exceptional importance in our study, as the rate of ID3 mutations in DLBCL is reported to be very low. Therefore a (un-)known mix of BL and DLBCL will not allow a robust estimate of the ID3 mutation rate in BL. Interestingly, Love et al. restricted their analyses to cases with proven MYC rearrangement. The rationale for that might be the attempt to enrich the analyzed cohort for BLs and to exclude DLBCLs, as the latter more infrequently harbor a MYC rearrangement. Despite these efforts, the rate of ID3 mutations in MYC positive lymphoma remains significantly different between the cohort reported by Love and colleagues and our cohort. Also not exactly known for the Love cohort, we expect that our cohort comprises much more pediatric B-NHL cases. Therefore the detected difference in the ID3 mutation rate might hint at a certain impact of patient age on the presence of absence of this mutation. In consequence, these data support the hypothesis of pathogenetic and biological differences between pediatric and adult BL.
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Functional characterization of STAT6 mutations in follicular lymphoma

Functional characterization of STAT6 mutations in follicular lymphoma

Luciferase reporter assay was performed by transient transfection of PARP14 promoter pGL3 constructs in 293T HEK cells as described before (chapter 2.2.7). 293T HEK cells were particular suitable, since they lack endogenous STAT6, yet express all other com- ponents of the IL-4 signaling cascade. 149 One day prior transfection, 150,000 cells per well were plated in 500 µl cell culture medium on 24-well plates. 200 ng PARP14 promo- ter pGL3 were co-transfected with 40 ng pRL Renilla luciferase control reporter vector and 1 ng, 10 ng, or 50 ng STAT6 wild-type or mutant pCIG expression vector. Controls included reactions without STAT6 pCIG construct and reactions with pGL3-Basic vector without PARP14 promoter region. To ensure comparable transfection efficiency across all reactions, equal amounts of DNA (290 ng) were transfected. Therefore, 50 ng, 49 ng, or 40 ng pCIG empty vector were transfected, as well. Table 2.25 lists all plasmids used in this experiment.
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Alemtuzumab-BEAM as conditioning for allogeneic hematopoietic stem cell transplantation in relapsed/refractory Hodgkin lymphoma: a single-center analysis

Alemtuzumab-BEAM as conditioning for allogeneic hematopoietic stem cell transplantation in relapsed/refractory Hodgkin lymphoma: a single-center analysis

The combination of alemtuzumab and BEAM as condi- tioning therapy before allogeneic HSCT showed promis- ing results in patients with follicular lymphoma and lym- phoproliferative disorders (Cull et al. 2000 ; Ingram et al. 2008 ). In this novel treatment scheme, alemtuzumab, a humanized monoclonal antibody to the panlymphoid anti- gen CD52, is combined with conventional chemotherapy with BEAM (carmustine, cytarabine, etoposide, and mel- phalan), a frequently used conditioning therapy in autolo- gous HSCT (Mills et al. 1995 ).

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Signature of deep mantle melting in South Iceland olivine

Signature of deep mantle melting in South Iceland olivine

Received: 1 December 2018 / Accepted: 26 April 2019 / Published online: 13 May 2019 © The Author(s) 2019 Abstract We present new high-precision major and trace element data on olivine macrocrysts from various volcano-tectonic settings in Iceland and use these data as a proxy for mantle mode and melting conditions. Within individual sampling sites examined (seven lavas and one tephra) olivine-dominated fractional crystallization, magma mixing and diffusive re-equilibration control observed variability in olivine composition. High-pressure fractional crystallization of clinopyroxene may have lowered Ca and increased Fe/Mn in one olivine population and subsolidus diffusion of Ni and Fe–Mg affected the mantle-derived Ni/Fo ratio in some compositionally zoned olivine macrocrysts. Interestingly, magmas erupted at the southern tip of the Eastern Volcanic Zone (SEVZ), South Iceland, have olivines with elevated Ni and low Mn and Ca contents compared to olivines from elsewhere in Iceland, and some of the SEVZ olivines have relatively low Sc and V and high Cr, Ti, Zn, Cu and Li in comparison to depleted Iceland rift tholeiite. In these olivines, the high Ni and low Mn indicate relatively deep melting (P final > 1.4 GPa, ~ 45 km), Sc, Ti and V are compatible with low-degree melts of lherzolite mantle, and elevated Zn may suggest modal (low-olivine) or geochemical (high Zn) enrichment in the source. The SEVZ olivine macrocrysts probably crystallized from magmas derived from olivine-bearing but relatively deep, enriched and fertile parts of the sub-Icelandic mantle, and indicate swift ascent of magma through the SEVZ lithosphere.
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Role of FOXO3 in classical Hodgkin lymphoma

Role of FOXO3 in classical Hodgkin lymphoma

lymphocyte-induced maturation protein-1) is regarded as master-regulator of PC development controlling the transcriptional network of terminal B cell differentiation. Initially, it was discovered as a repressor of beta-interferon gene expression (Keller and Maniatis 1991) but its major role during B cell development became only clear afterwards (Turner et al. 1994; Shapiro-Shelef et al. 2003). It is a member of the PRDM protein family inheriting the highly conserved PR domain (Xie et al. 1997) and is a subclass of the SET domain showing histone methyltransferase (HMT) activity (Dillon et al. 2005). The human BLIMP1 protein also contains five Krüppel-type zinc finger domains for DNA-binding located at the C terminal end of the protein, the consensus binding site called PRDI site, a proline-rich region and two acidic regions (Figure 2). Via its zinc finger motif and the proline rich region, Blimp-1 can act as a transcriptional repressor (Keller and Maniatis 1991) through association with corepressors such as Groucho family members (Ren et al. 1999), histone deacetylases (Yu et al. 2000) and the histone H3 methyltransferase G9a leading to a silencing histone modification (Gyory et al. 2004). The PRDI site with a size of 11bp and the sequence (A/C)AG(T/C)GAAAG(T/C)(G/T) has analogies to the binding sites of IRF (interferon regulatory factor)1 and IRF2 and the ability to bind to the same regulatory sites (Kuo and Calame 2004; Boi et al. 2015).
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Genome-Wide Analysis of Interchromosomal Interaction Probabilities Reveals Chained Translocations and Overrepresentation of Translocation Breakpoints in Genes in a Cutaneous T-Cell Lymphoma Cell Line

Genome-Wide Analysis of Interchromosomal Interaction Probabilities Reveals Chained Translocations and Overrepresentation of Translocation Breakpoints in Genes in a Cutaneous T-Cell Lymphoma Cell Line

Keywords: chromosome conformation capture, chromoplexy, chromosomal translocations, deep sequencing, cutaneous T-cell lymphoma inTrODUcTiOn The analysis of structural chromosomal aberrations is of relevance for both basic and translational research. Several chromosomal markers are already routinely used in clinical tests for genotype-based sub-classification of tumors or to assist in therapeutic decisions. In addition, the identification of recur- rent aberrations can highlight driver genes of tumorigenesis, which represent promising starting points for the development of targeted therapies. Apart from clinical applications, the char- acterization of chromosomal aberrations can shed light on the underlying mutational mechanisms and in this way contribute to a better understanding of the cause and course of intra- individual evolution of tumors.
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VEGFR2 and VEGFA polymorphisms are not associated with an inferior prognosis in Caucasian patients with aggressive B-cell lymphoma

VEGFR2 and VEGFA polymorphisms are not associated with an inferior prognosis in Caucasian patients with aggressive B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common non- Hodgkin's lymphoma. The addition of the CD20 antibody rituximab to conventional chemotherapy has substantially improved the out- come of these patients in the last 15 years and is now the standard of care. 1-5 Despite this improvement, more than 30% of patients with DLBCL will ultimately relapse and are in need for a salvage treatment. 6 The International Prognostic Index (IPI), which was in- troduced in 1993, 7 is still the standard clinical tool to predict out- comes in patients with aggressive lymphomas. 8 Nevertheless, there is a constant pursuit of new prognostic markers, for example, ABC and GCB, 9 vitamin D, 10 or Fc-gamma receptor. 11 Angiogenesis is of utmost importance in the progression of many malignancies. The vascular endothelial growth factor (VEGF) is known as a regulator of endothelial cell proliferation and plays a major role in angiogen- esis. 12 Furthermore, single-nucleotide polymorphisms (SNP) of the VEGF pathway have been associated with incidence and prognosis of many solid and hematologic malignancies, 13,14 and the inhibition of angiogenesis pathways for example by VEGF antibodies or tyros- ine kinase inhibitors has shown clinical benefit in colon 15 and kid- ney cancer. 16,17 In addition, VEGF and its cellular receptor, and the vascular endothelial growth factor receptor type 2 (VEGFR2) play a key role in leukemia-associated angiogenesis, 18 and the VEGF gene (VEGFA) polymorphism was reported to predict the prognosis in pa- tients with acute myeloid leukemia patients. 19 Despite the success of VEGF antibodies for the treatment of solid tumors, it failed to prove its efficacy in hematologic neoplasias like DLBCL. Previously published studies showed no significant treatment effect of bevaci- zumab whether as a single agent in patients with relapsed, aggres- sive non-Hodgkin lymphoma 20 or in combination with R-CHOP as first-line treatment for patients with aggressive B-cell lymphoma. 21 There have been several reports in the literature 22-24 that in aggres- sive lymphoma, in particular in DLBCL, high VEGF serum levels, and elevated expression of VEGF in tissue biopsies are associated with a higher tumor burden and inferior overall survival (OS). Kim et al ob- served in a Korean population of lymphoma patients that the VEGF- receptor 2 polymorphism rs1870377 major allele TT had an inferior prognosis. It was hypothesized that the inferior binding of minor allele AA to VEGF impaired lymphoma angiogenesis and conferred the benefit. 25 Therefore, the aim of this study was to investigate the effects of VEGF and VEGF-receptor polymorphisms on the progno- sis of Caucasian patients with aggressive B-cell lymphoma treated with R-CHOP protocol within the prospective RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).
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The influence of magma ocean crystallization on mantle dynamics

The influence of magma ocean crystallization on mantle dynamics

The Earth’s mantle is 1.7 times as deep as Mars’s, which increases the reference Rayleigh number by a factor 5. Although it formed from a volatile-depleted zone of the protoplanetary disc (Carlson et al., 2014), and the mechanisms involved in the delivery of volatile on Earth are not clearly identified, it is likely that Earth’s water content was delivered during planetary formation (Morbidelli, Lunine, O’Brien, Raymond, & Walsh, 2012a), so that it was already available by the time of the magma ocean solidification. The Earth can thus have developed a thick blanketing atmosphere, able to sustain a long-lived magma ocean (Abe, 1997; Zahnle et al., 2007; Lebrun et al., 2013; Nikolaou et al., 2019, e.g.). According to our results, a late magma ocean on Earth is likely to have experienced solid cumulate mixing during its crystallization, resulting in a roughly homogeneous mantle structure, even though the pressure dependence of the rheology, more relevant for the Earth than for Mars because of the higher pressure range, may have caused a less efficient mixing of the lower mantle. These findings are corroborated by (Ballmer et al., 2017), who performed similar simulations but using a more realistic iron fractionation model and a simplified (isoviscous) rheology. As noted in Section 1.3.2.6, the bottom-up crystallization scenario might not be applicable to the Earth, due to either the melting curve gradient becoming less steep than the adiabat at high pressures (Stixrude, de Koker, Sun, Mookherjee, & Karki, 2009) or the density cross-over between solid and liquid due to enrichment of melts in iron (Boukaré et al., 2015). Modelling the latter effect, Miyazaki and Korenaga (2019) showed that, depending on the efficiency of crystal settling and cumulates compaction (which they found to be decisive for the fate of iron distribution), sub-mantle scale Rayleigh-Taylor instability was also likely to affect the thermal structure of the mantle, in favour of mantle mixing and potentially formation of a long-lived basal magma ocean (Labrosse et al., 2007; Laneuville et al., 2018). This scenario still has to be compared with present-day possible traces of a past magma ocean, in particular with the presence of large low-shear-velocity provinces at the core mantle boundary (e.g. Garnero, McNamara, & Shim, 2016). Interpreted in the light of post magma ocean solidification dynamics, they could represent remnants of a long-lived basal magma ocean, or overturned cumulates of a bottom-up solidified mantle (Ballmer et al., 2017).
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Prognostic analysis of interim 18F-FDG PET/CT in patients with diffuse large B cell lymphoma after one cycle versus two cycles of chemotherapy

Prognostic analysis of interim 18F-FDG PET/CT in patients with diffuse large B cell lymphoma after one cycle versus two cycles of chemotherapy

Diffuse large B cell lymphoma (DLBCL) is a highly aggressive neoplasm and the most common subtype of non-Hodgkin’s lymphoma (NHL) [ 1 , 2 ]. Cytotoxic chemotherapy regimens can achieve complete remission. However, it is crucial to iden- tify non-responders and high-risk patients, since lymphomas may be histologically, immunohistochemically, and genetically heterogeneous, making them resistant to chemotherapy [ 3 ]. This heterogeneity results in the relapse or progression of 50% of DLBCLs during or after standard treatment [ 4 ]. Therefore, it is important to detect patients who will not be sensitive to chemotherapy at an early time point and to guide clinical therapeutic strategies.
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New perspectives in extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue: the Vienna experience / submitted by Barbara Kiesewetter-Wiederkehr

New perspectives in extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue: the Vienna experience / submitted by Barbara Kiesewetter-Wiederkehr

A very different but truly elegant immunomodulatory approach for the treatment of MALT lymphoma is the use of clarithromycin, a macrolide antibiotic used also in the basic eradication regimen for H. pylori positive gastric disease [15,16]. Based on in vivo and in in vitro data, clarithromycin entails not only antimicrobial but also immunomodulatory and direct anti-proliferative effects; it has been shown to enhance antitumor activity of macrophages, NK-cells and cytotoxic T-cells; reduce neutrophil production of IL6, decrease TNF-alpha and VEGF levels and induce pro-apoptotic changes in B-cells [155]. In terms of clinical data, anti- tumor activity of clarithromycin in combination with IMiDs has been documented for MM patients and it seemed that the combination is safe and active, and possibly helps to overcome IMiD resistance in previously treated patients [156,157]. However, the effect of monotherapy was small in MM [158]. For MALT lymphoma, different regimens have been tested, ranging from 1g daily for 6 months continuously to 2g daily for two weeks in a five week cycle, with the latter being tested in the “high-dose clarithromycin trial” (HD-K trial) for relapsed refractory MALT lymphoma [110,111,159,160]. In all reported series, potential co- infection with H. pylori had previously been ruled out to prevent a bias by antimicrobial effects. ORR was 52% (95% CI 32-72) and 2-year PFS 56% (+/- 10%) in the HD-K trial (number of patients = 23) published last year with contribution of Univ.-Prof. Raderer’s study group [111]. These data are in the range of efficacy reported in other series. A current matter of debate is the optimal dosing of clarithromycin, but based on a retrospective analysis which was again performed in cooperation of our department and the San Raffaele Scientific
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The role of microRNA in FOXO1 repression in classical Hodgkin Lymphoma

The role of microRNA in FOXO1 repression in classical Hodgkin Lymphoma

The ways cancer uses miRNAs to evolve are manifold. Genetic alterations are frequently observed, for example when microRNAs were first linked to cancer, it was found that miR-15 and miR-16 were deleted in more than half of B cell chronic lymphocytic leukemias (Calin et al. 2002). But also variation of the 3´UTR binding sites of target mRNAs is a common feature of cancer (Ziebarth et al. 2012), as well as single nucleotide polymorphisms in miRNAs that thereby alter their biological function (Sun et al. 2009). Alterations of the miRNA processing machinery can lead to the global reduction of microRNAs; a well-known feature observed in cancer (Allegra et al. 2014; Lu et al. 2005; Melo et al. 2010; Wegert et al. 2015). Interestingly, the repression of Dicer is also associated with an invasive phenotype and drug resistance in ovarian cancer (Kuang et al. 2013). A very striking way of altering miRNA action in cancer is by redirecting the RISC with so- called competing endogenous RNAs. These RNAs display multiple miRNA binding sites that act competitively in order to block specific miRNA action (Hayes et al. 2014). As an example, circular CDR1 (cerebellar degeneration-related protein 1) RNA contains more than 60 binding sites for a miR-7, a microRNA that acts as a tumor suppressor (Hansen et al. 2013; Memczak et al. 2013). Basically, alterations of genes, RNA or proteins can occur on any level in cancer and we have, by far, not yet reached an integral understanding of its complexity. There are many more mechanisms of miRNA alterations in cancer, but here is to mention only some. FOXO1 has been identified as a tumor suppressor in breast cancer and subsequent miRNA studies were conducted, identifying 3 distinct miRNAs, miR- 27a, miR-96 and miR-182, that led to a decrease in FOXO1 mRNA (Guttilla and White 2009). Since FOXO1 has also been identified to be downregulated in cHL by our group (Xie et al. 2012), it was of particular interest to investigate whether miRNAs contribute to FOXO1 repression in this lymphoma entity.
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Analysing two potential outlets of a shrinking Pacific mantle reservoir

Analysing two potential outlets of a shrinking Pacific mantle reservoir

southeastern Atlantic Ocean and parts of the African continent by as much as ~ 1km (Lithgow- Bertelloni and Silver, 1998) in the so-called African superswell (Nyblade and Robinson, 1994), is particularly well known. Geodynamic studies favor a substantial hotspot contribution to the mantle energy budget (Bunge et al., 2001). Also, a significant role of plumes in general mantle circulation would adequately explain the nature of the prominent seismic low velocity anomaly harbored in the deep mantle beneath Africa (Schuberth et al., 2009 a, b). The elevated topography of the African superswell contrasts with significant negative dynamic topography of up to ~ 1 km inferred for the conjugate South American margin in the Argentine Basin (Fig. 8) (e.g., Winterbourne et al., 2009). The remarkable dynamic topography gradient across the South Atlantic is consistent with westward flow emanating from the African superplume, as suggested by Behn et al. (2004) and Husson et al. (2012), rather than eastward flow through the Drake Passage. Equally important is the fact that the magnitude of the basal shear tractions associated with westward fluxing subatlantic asthenosphere may be sufficient to balance the budget of driving and resisting forces acting on the South American plate (Iaffaldano and Bunge, 2009). Thus a variety of evidence suggests that mass balance between the Pacific and Atlantic mantle domains is achieved through deep mantle processes rather than shallow upper mantle flux in the asthenosphere.
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Overturn of ilmenite‐bearing cumulates in a rheologically weak lunar mantle

Overturn of ilmenite‐bearing cumulates in a rheologically weak lunar mantle

A limitation of our models is the choice of 2-D geometry (half cylinder with free-slip and insulating side- walls), which was required in order to properly resolve the deformation of the thin IBC layer. The effects of a 3-D geometry could be twofold. On the one hand, Guerrero et al. (2018) recently compared simulations of stagnant lid convection carried out in 2-D spherical annuli (Hernlund & Tackley, 2008) and 3-D spherical shells. Particularly for small core-to-planet radius ratios such as that of the Moon, the authors showed that 2-D (statistical steady state) solutions systematically overestimate the mantle temperature. If this were actu- ally the case despite the short time scale we dealt with in our study, our conclusions on the need of a weak lunar rheology would be strengthened. A cooler mantle would have a higher viscosity, which would ease the formation of the stagnant lid and hinder the IBC overturn. Therefore, even lower-reference viscosities or activation energies might be required. On the other hand, small cores tend to promote the formation of low-degree (possibly degree-one) structures in 3-D isochemical thermal convection (Guerrero et al., 2018; Yao et al., 2014). The IBC overturn is driven by a compositional instability, which, as previously discussed in this section, is likely to grow according to a small wavelength comparable to the IBC thickness. Yet this remains to be ultimately tested with high-resolution 3-D simulations of thermochemical convection.
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Left ventricular thrombus in a patient with cutaneous T-cell lymphoma, hypereosinophilia and Mycoplasma pneumoniae infection a challenging diagnosis: a case report

Left ventricular thrombus in a patient with cutaneous T-cell lymphoma, hypereosinophilia and Mycoplasma pneumoniae infection a challenging diagnosis: a case report

Because scintillating scotomas occurred in the left visual field, cranial CT and MRI were performed. The latter confirmed the presence of two small point-shaped lesions, one in the right cerebellar hemisphere and one in the right precentral gyrus, consistent with a recent embolic/ischemic event. Five days after the initial TTE, cardiac MRI showed that the mass had shrunk to a con- siderably smaller size (diameter: approx. 10 mm), free- floating and pedunculated, arising from the lateral wall (Figure 1b). An additional echocardiographic cine-loop shows this in more detail (see Additional file 2). In com- bination with the diagnostic finding of the fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomog- raphy/CT, the suspect hypertrophic apical region seemed consistent with an infiltrative process of the lymphoma. The myocardium was thickened and there was a grayish discoloration of the tissue. The akinesia described earlier was not detectable anymore. In the repeat TTE per- formed one day later, the suspect hypertrophic apical region seemed consistent with endomyocardial fibro- sis. Echocardiographic findings leading to the picture of endomyocardial fibrosis included the combination of myocardial thickening, a thrombus adherent to the endocardial surface, and enlargement of the left atrium. The patient received anticoagulation therapy between the imaging procedures showing reduction in size of the intracardiac mass.
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