The sole distinguishing feature of follicular lymphoma grade 3B and diffuse large B-cell lymphoma is the growth pattern assessed by histopathology analysis. Diffuse growth defines diffuse large ...B-cell lymphoma but the clinical relevance of this finding when occurring in follicular lymphoma grade 3B is uncertain. To address this question, individual and coexisting follicular lymphoma grade 3B and diffuse large B-cell lymphoma were separated and analyzed for immunophenotype and molecular genetic features by fluorescence in situ hybridization, targeted sequencing and gene expression profiling. Clinical features of follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma were studied in homogeneously treated patients from a prospective randomized trial. Follicular lymphoma grade 3B and diffuse large B-cell lymphoma frequently show intermediate growth pattern and/or occurred simultaneously in the same tissue at the time of initial diagnosis. When occurring simultaneously follicular lymphoma grade 3B and diffuse large B-cell lymphoma do not differ significantly in genetic aberrations or phenotype but distinct features in gene expression reflect divergent microenvironment. Follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma do not differ in major clinical parameters such as international prognostic index, response to immunochemotherapy, progression or overall survival. Follicular lymphoma grade 3B and simultaneous diffuse large B-cell lymphoma are molecularly homogenous. Histological detection of diffuse large B-cell lymphoma is not associated with features of a more aggressive disease and does not reflect transformation or progression of follicular lymphoma Grade 3B.
Cell walls are not only a protective barrier surrounding protoplasts but serve as signaling platform between the extracellular environment and the intracellular physiology. Ions of heavy metals and ...trace elements, summarized to metal ions, bind to cell wall components, trigger their modification and provoke growth responses. To examine if metal ions trigger cell wall sensing receptor like kinases (RLKs) of the
Catharanthus roseus
RLK1-like (
Cr
RLK1L) family we employed a molecular genetic approach. Quantitative transcription analyses show that
HERCULES1 (HERK1)
,
THESEUS1 (THE1)
, and
FERONIA (FER)
were differently regulated by cadmium (Cd), nickel (Ni), and lead (Pb). Growth responses were quantified for roots and etiolated hypocotyls of related mutants and overexpressors on Cd, copper (Cu), Ni, Pb, and zinc (Zn) and revealed a complex pattern of gene specific, overlapping and antagonistic responses. Root growth was often inversely affected to hypocotyl elongation. For example, both
HERK
genes seem to negatively regulate hypocotyl elongation upon Cd, Ni, Zn, and Pb while they support root growth on Cd, Cu, and Ni. The different
THE1
alleles exhibited a similar effect between roots and hypocotyls on Ni, where the loss-of-function mutant was more tolerant while the gain of function mutants were hypersensitive indicating that
THE1
is mediating Ni specific inhibition of hypocotyl elongation in the dark. In contrast hypocotyl elongation of the knock-out mutant,
fer-4
, was hypersensitive to Ni but exhibited a higher tolerance to Cd, Cu, Pb, and Zn. These data indicate an antagonistic action between THE1 and FER in relation to hypocotyl elongation upon excess of Ni. FERs function as receptor for rapid alkalinization factors (RALFs) was tested with the indicator bromocresol purple. While
fer-4
roots strongly acidified control and metal ion containing media, the etiolated hypocotyls alkalized the media which is consistent with the already shorter hypocotyl of
fer-4
. No other
CrRLK1L
mutant exhibited this phenotype except of the THE1:GFP overexpressor on Ni suggesting that THE1 might be involved in Ni induced and hypocotyl specific RALF signaling and growth regulating pathway. Overall, our findings establish a molecular link between metal ion stress, growth and the cell wall integrity sensors of the
Cr
RLK1L family.
Members of the highly conserved and ubiquitously expressed pleiotropic CK1 family play major regulatory roles in many cellular processes including DNA-processing and repair, proliferation, ...cytoskeleton dynamics, vesicular trafficking, apoptosis, and cell differentiation. As a consequence of cellular stress conditions, interaction of CK1 with the mitotic spindle is manifold increased pointing to regulatory functions at the mitotic checkpoint. Furthermore, CK1 is able to alter the activity of key proteins in signal transduction and signal integration molecules. In line with this notion, CK1 is tightly connected to the regulation and degradation of β-catenin, p53, and MDM2. Considering the importance of CK1 for accurate cell division and regulation of tumor suppressor functions, it is not surprising that mutations and alterations in the expression and/or activity of CK1 isoforms are often detected in various tumor entities including cancer of the kidney, choriocarcinomas, breast carcinomas, oral cancer, adenocarcinomas of the pancreas, and ovarian cancer. Therefore, scientific effort has enormously increased (i) to understand the regulation of CK1 and its involvement in tumorigenesis- and tumor progression-related signal transduction pathways and (ii) to develop CK1-specific inhibitors for the use in personalized therapy concepts. In this review, we summarize the current knowledge regarding CK1 regulation, function, and interaction with cellular proteins playing central roles in cellular stress-responses and carcinogenesis.
Abstract
While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at ...relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While
TP53
and
CCND3
mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in
ID3
,
DDX3X, ARID1A
and
SMARCA4
, while several genes such as
BCL2
and
YY1AP1
are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that
TP53
mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.
The prognosis of germinal center–derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable ...outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.
SARS-CoV-2 causes substantial morbidity and mortality in elderly and immunocompromised individuals, particularly in retirement homes, where transmission from asymptomatic staff and visitors may ...introduce the infection. Here we present a cheap and fast screening method based on direct RT-qPCR to detect SARS-CoV-2 in single or pooled gargle lavages ("mouthwashes"). This method detects individuals with large viral loads (Ct≤29) and we use it to test all staff at a nursing home daily over a period of three weeks in order to reduce the risk that the infection penetrates the facility. This or similar approaches can be implemented to protect hospitals, nursing homes and other institutions in this and future viral epidemics.
Die Berühmtheit eines Wissenschaftlers lässt sich nicht ausschließlich an der Anzahl der auf seine Werke getätigten Verweise ermessen. Auch die Vernachlässigung der Vollständigkeit eines Verweises ...auf den Urheber einer als grundlegend wahrgenommenen Idee stellt eine - wenn nicht gar die intensivste - Form der Anerkennung dar.Julia Richter ermittelt, mit welchen Strategien wissenschaftliches Prestige erzeugt wird. Im Zentrum ihrer Analyse stehen die Verweise auf Ferdinand de Saussure im Diskurs der romanistischen Linguistik.Die Studie entwickelt sogleich eine diskursanalytische Methode, die geeignet ist, Verweise in wissenschaftlichen Texten auf ihr Potential hin zu untersuchen, bestimmte Akteure des Diskurses aufzuzeigen und die Beziehungen zwischen diesen Diskursakteuren darzustellen.
Mammalian genomes contain many repetitive elements, including long terminal repeats (LTRs), which have long been suspected to have a role in tumorigenesis. Here we present evidence that aberrant LTR ...activation contributes to lineage-inappropriate gene expression in transformed human cells and that such gene expression is central for tumor cell survival. We show that B cell-derived Hodgkin's lymphoma cells depend on the activity of the non-B, myeloid-specific proto-oncogene colony-stimulating factor 1 receptor (CSF1R). In these cells, CSF1R transcription initiates at an aberrantly activated endogenous LTR of the MaLR family (THE1B). Derepression of the THE1 subfamily of MaLR LTRs is widespread in the genome of Hodgkin's lymphoma cells and is associated with impaired epigenetic control due to loss of expression of the corepressor CBFA2T3. Furthermore, we detect LTR-driven CSF1R transcripts in anaplastic large cell lymphoma, in which CSF1R is known to be expressed aberrantly. We conclude that LTR derepression is involved in the pathogenesis of human lymphomas, a finding that might have diagnostic, prognostic and therapeutic implications.
Neddylation is a ubiquitylation-like pathway that controls cell cycle and proliferation by covalently conjugating Nedd8 to specific targets. However, its role in neurons, nonreplicating postmitotic ...cells, remains unexplored. Here we report that Nedd8 conjugation increased during postnatal brain development and is active in mature synapses, where many proteins are neddylated. We show that neddylation controls spine development during neuronal maturation and spine stability in mature neurons. We found that neddylated PSD-95 was present in spines and that neddylation on Lys202 of PSD-95 is required for the proactive role of the scaffolding protein in spine maturation and synaptic transmission. Finally, we developed Nae1(CamKIIα-CreERT2) mice, in which neddylation is conditionally ablated in adult excitatory forebrain neurons. These mice showed synaptic loss, impaired neurotransmission and severe cognitive deficits. In summary, our results establish neddylation as an active post-translational modification in the synapse regulating the maturation, stability and function of dendritic spines.
PDF
