80 research outputs found
CD40 Ligand and Autoantigen Are Involved in the Pathogenesis of Low-Grade B-Cell Lymphomas of Mucosa-Associated Lymphoid Tissue
Low-grade MALT-type lymphomas are malignancies of mucosal marginal-zone B cells
and preceded by reactive inflammatory lymphoid tissue. Experimental observations suggest that antigen
and CD40 Ligand act during cognate T/B cell interaction and are crucial for germinal center B-cell maturation
generating marginal-zone B cells. To investigate the mechanisms underlying the development of extranodal MALT-type lymphomas, the immunoglobulin receptor was sequenced and analyzed for antigen specificity using heterohybridoma technology.
Furthermore, CD40 ligand expression was evaluated by immunohistochemistry and by semiquantitative RT-PCR,
and ligand binding to the CD40 of tumor B cells was studied using the CD40 system. Hypermutations were found in low-grade
lymphomas throughout CDR1- CDR3 suggestive of positive selection through their antigen receptor.
Different VH families were used and more than 69% of tumor immunoglobulins bound different mucosal antigens.
CD40L expression was found in the tumor marginal zone in substantial amounts.
The in vitro proliferation response of all low-grade MALT-type lymphomas was dependent on
anti-CD40- mediated signals and cytokines. Our data provide evidence that autoantigen as well as the CD40L
expressed by activated nonneoplastic T cells may drive the evolution of low-grade MALT-type lymphomas either
directly or by paracrine mechanisms and that antigen may contribute to lymphoma pathogenesis
On the adiabatic behaviour for a Wigner-Weisskopf atom (Spectral and Scattering Theory and Related Topics)
In this research announcement we present some recent results of the authors on the adiabatic theorem for a system without a spectral gap [4]
Descent of Equivalences and Character Bijections
Categorical equivalences between block algebras of finite groups—such as Morita and derived equivalences—are well known to induce character bijections which commute with the Galois groups of field extensions. This is the motivation for attempting to realise known Morita and derived equivalences over non-splitting fields. This article presents various results on the theme of descent to appropriate subfields and subrings. We start with the observation that perfect isometries induced by a virtual Morita equivalence induce isomorphisms of centres in non-split situations and explain connections with Navarro’s generalisation of the Alperin–McKay conjecture. We show that Rouquier’s splendid Rickard complex for blocks with cyclic defect groups descends to the non-split case. We also prove a descent theorem for Morita equivalences with endopermutation source
Sex differentiation in grayling (Salmonidae) goes through an all-male stage and is delayed in genetic males who instead grow faster.
Fish populations can be threatened by distorted sex ratios that arise during sex differentiation. Here we describe sex differentiation in a wild grayling (Thymallus thymallus) population that suffers from distorted sex ratios. We verified that sex determination is linked to the sex determining locus (sdY) of salmonids. This allowed us to study sex-specific gene expression and gonadal development. Sex-specific gene expression could be observed during embryogenesis and was strong around hatching. About half of the fish showed immature testes around eleven weeks after fertilization. This phenotype was mostly replaced by the "testis-to-ovary" or "ovaries" phenotypes during development. The gonads of the remaining fish stayed undifferentiated until six months after fertilization. Genetic sexing revealed that fish with undifferentiated gonads were all males, who grew larger than the genetic females during the observational period. Only 12% of the genetic males showed testicular tissue six months after fertilization. We conclude that sex differentiation starts before hatching, goes through an all-male stage for both sexes (which represents a rare case of "undifferentiated" gonochoristic species that usually go through an all-female stage), and is delayed in males. During these juvenile stages males grow faster than females instead of developing their gonads
Muscle RING-finger 2 and 3 maintain striated-muscle structure and function
Background: The Muscle-specific RING-finger (MuRF) protein family of E3 ubiquitin ligases is important for maintenance of muscular structure and function. MuRF proteins mediate adaptation of striated muscles to stress. MuRF2 and MuRF3 bind to microtubules and are implicated in sarcomere formation with noticeable functional redundancy. However, if this redundancy is important for muscle function in vivo is unknown. Our objective was to investigate cooperative function of MuRF2 and MuRF3 in the skeletal muscle and the heart in vivo. Methods: MuRF2 and MuRF3 double knockout mice (DKO) were generated and phenotypically characterized. Skeletal muscle and the heart were investigated by morphological measurements, histological analyses, electron microscopy, immunoblotting, and real-time PCR. Isolated muscles were subjected to in vitro force measurements. Cardiac function was determined by echocardiography and working heart preparations. Function of cardiomyocytes was measured in vitro. Cell culture experiments and mass-spectrometry were used for mechanistic analyses. Results: DKO mice showed a protein aggregate myopathy in skeletal muscle. Maximal force development was reduced in DKO soleus and extensor digitorum longus. Additionally, a fibre type shift towards slow/type I fibres occurred in DKO soleus and extensor digitorum longus. MuRF2 and MuRF3-deficient hearts showed decreased systolic and diastolic function. Further analyses revealed an increased expression of the myosin heavy chain isoform beta/slow and disturbed calcium handling as potential causes for the phenotype in DKO hearts. Conclusions: The redundant function of MuRF2 and MuRF3 is important for maintenance of skeletal muscle and cardiac structure and function in vivo
Combination therapy with crizotinib and vinblastine for relapsed or refractory pediatric ALK-positive anaplastic large cell lymphoma
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Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.
Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL
Between the Vinča and Linearbandkeramik worlds: the diversity of practices and identities in the 54th–53rd centuries cal BC in south-west Hungary and beyond
Szederkény-Kukorica-dűlő is a large settlement in south-east Transdanubia, Hungary, excavated in advance of road construction, which is notable for its combination of pottery styles, variously including Vinča A, Ražište and LBK, and longhouses of a kind otherwise familiar from the LBK world. Formal modelling of its date establishes that the site probably began in the later 54th century cal BC, lasting until the first decades of the 52nd century cal BC. Occupation, featuring longhouses, pits and graves, probably began at the same time on the east and west parts of the settlement, the central part starting a decade or two later; the western part was probably abandoned last. Vinča pottery is predominantly associated with the east and central parts of the site, and Ražište pottery with the west. Formal modelling of the early history and diaspora of longhouses in the LBK world suggests their emergence in the Formative LBK of Transdanubia c. 5500 cal BC and then rapid diaspora in the middle of the 54th century cal BC, associated with the ‘earliest’ (älteste) LBK. The adoption of longhouses at Szederkény thus appears to come a few generations after the start of the diaspora. Rather than explaining the mixture of things, practices and perhaps people at Szederkény by reference to problematic notions such as hybridity, we propose instead a more fluid and varied vocabulary including combination and amalgamation, relationships and performance in the flow of social life, and networks; this makes greater allowance for diversity and interleaving in a context of rapid change
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