193 research outputs found
L-invariants for cohomological representations of PGL(2) over arbitrary number fields
No full textGehrmann L, Pati MR. L-invariants for cohomological representations of PGL(2) over arbitrary number fields. Forum of Mathematics, Sigma. 2024;12: e71.**Abstract**
Let
be a cuspidal, cohomological automorphic representation of an inner form
G
of
over a number field
F
of arbitrary signature. Further, let
be a prime of
F
such that
G
is split at
and the local component
of
at
is the Steinberg representation. Assuming that the representation is noncritical at
, we construct automorphic
-invariants for the representation
. If the number field
F
is totally real, we show that these automorphic
-invariants agree with the Fontaine–Mazur
-invariant of the associated
p
-adic Galois representation. This generalizes a recent result of Spieß respectively Rosso and the first named author from the case of parallel weight
to arbitrary cohomological weights.
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Was bedeutet: Unbedingte Anerkennung der Andersheit des Anderen? Intersexualität und Transidentität im Licht advokatorischer Ethik
No full textIntegration of pathway knowledge into a reweighted recursive feature elimination approach for risk stratification of cancer patients
No full textAbstract
Motivation: One of the main goals of high-throughput gene-expression studies in cancer research is to identify prognostic gene signatures, which have the potential to predict the clinical outcome. It is common practice to investigate these questions using classification methods. However, standard methods merely rely on gene-expression data and assume the genes to be independent. Including pathway knowledge a priori into the classification process has recently been indicated as a promising way to increase classification accuracy as well as the interpretability and reproducibility of prognostic gene signatures.
Results: We propose a new method called Reweighted Recursive Feature Elimination. It is based on the hypothesis that a gene with a low fold-change should have an increased influence on the classifier if it is connected to differentially expressed genes. We used a modified version of Google's PageRank algorithm to alter the ranking criterion of the SVM-RFE algorithm. Evaluations of our method on an integrated breast cancer dataset comprising 788 samples showed an improvement of the area under the receiver operator characteristic curve as well as in the reproducibility and interpretability of selected genes.
Availability: The R code of the proposed algorithm is given in Supplementary Material.
Contact: [email protected]; [email protected]
Supplementary information: Supplementary data are available at Bioinformatics online.</jats:p
Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells
No full textHypoxia is well known to limit curability of tumors by ionizing radiation. Here, we show that hypoxia treatment of tumor cells causes coexpression of heat shock protein 70 (Hsp70) and phosphatidylserine (PS) on the cell surface. Colocalization of Hsp70 and PS, as determined by confocal microscopy, also occurs when exogenous FITC-labeled Hsp70 protein is added to normoxic and hypoxic tumor cells. Moreover, the interaction of Hsp70 with PS was demonstrated in artificial unilamellar phosphatidylcholine/ phosphatidylserine (PC/PS) liposomes at the physiological ratio of 8/2. Indeed, the Hsp70-liposome interaction gradually increased with elevating PS molar ratios (8/2 > or = 7/3 < 5/5 < 4/6 < 3/7 < 2/8). In contrast, only a weak Hsp70 interaction was detected in phosphatidylcholine/phosphatidylglycerol (PC/PG) liposomes, thus demonstrating that the interaction was not a charge-related effect. The interaction of Hsp70 with surface PS significantly reduces clonogenic cell survival in normoxic (EC(50) of Hsp70=85 microg/ml) and hypoxic (EC(50) of Hsp70=55 microg/ml) tumor cells. The radiation-induced tumor cell killing was significantly enhanced by the addition of Hsp70 protein (50 microg/ml). Since apoptosis was not significantly enhanced in normoxic and hypoxic tumor cells by the addition of Hsp70, we hypothesize that the Hsp70 protein-induced reduction in clonogenic cell survival might be through necrosis rather than apoptosis
Tumor-specific Hsp70 plasma membrane localization is enabled by the glycosphingolipid Gb3
No full textHuman tumors differ from normal tissues in their capacity to present Hsp70, the major stress-inducible member of the HSP70 family, on their plasma membrane. Membrane Hsp70 has been found to serve as a prognostic indicator of overall patient survival in leukemia, lower rectal and non small cell lung carcinomas. Why tumors, but not normal cells, present Hsp70 on their cell surface and the impact of membrane Hsp70 on cancer progression remains to be elucidated.Although Hsp70 has been reported to be associated with cholesterol rich microdomains (CRMs), the partner in the plasma membrane with which Hsp70 interacts has yet to be identified. Herein, global lipid profiling demonstrates that Hsp70 membrane-positive tumors differ from their membrane-negative counterparts by containing significantly higher amounts of globotriaoslyceramide (Gb3), but not of other lipids such as lactosylceramide (LacCer), dodecasaccharideceramide (DoCer), galactosylceramide (GalCer), ceramide (Cer), or the ganglioside GM1. Apart from germinal center B cells, normal tissues are Gb3 membrane-negative. Co-localization of Hsp70 and Gb3 was selectively determined in Gb3 membrane-positive tumor cells, and these cells were also shown to bind soluble Hsp70-FITC protein from outside in a concentration-dependent manner. Given that the latter interaction can be blocked by a Gb3-specific antibody, and that the depletion of globotriaosides from tumors reduces the amount of membrane-bound Hsp70, we propose that Gb3 is a binding partner for Hsp70. The in vitro finding that Hsp70 predominantly binds to artificial liposomes containing Gb3 (PC/SM/Chol/Gb3, 17/45/33/5) confirms that Gb3 is an interaction partner for Hsp70.These data indicate that the presence of Gb3 enables anchorage of Hsp70 in the plasma membrane of tumors and thus they might explain tumor-specific membrane localization of Hsp70
Big principal series, -adic families and -invariants
No full textGehrmann L, Rosso G. Big principal series, -adic families and -invariants. Compositio Mathematica. 2022;158(2):409-436.
In earlier work, the first named author generalized the construction of Darmon-style
-invariants to cuspidal automorphic representations of semisimple groups of higher rank, which are cohomological with respect to the trivial coefficient system and Steinberg at a fixed prime. In this paper, assuming that the Archimedean component of the group has discrete series we show that these automorphic
-invariants can be computed in terms of derivatives of Hecke eigenvalues in
-adic families. Our proof is novel even in the case of modular forms, which was established by Bertolini, Darmon and Iovita. The main new technical ingredient is the Koszul resolution of locally analytic principal series representations by Kohlhaase and Schraen. As an application of our results we settle a conjecture of Spieß: we show that automorphic
-invariants of Hilbert modular forms of parallel weight
are independent of the sign character used to define them. Moreover, we show that they are invariant under Jacquet–Langlands transfer and, in fact, equal to the Fontaine–Mazur
-invariant of the associated Galois representation. Under mild assumptions, we also prove the equality of automorphic and Fontaine–Mazur
-invariants for representations of definite unitary groups of arbitrary rank. Finally, we study the case of Bianchi modular forms to show how our methods, given precise results on eigenvarieties, can also work in the absence of discrete series representations.
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Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages
No full textHeat shock proteins (hsps) are intracellular chaperones that play a key role in the recovery from stress. Hsp70, the major stress-induced hsp, has been found in the extracellular medium and is capable of activating immune cells. The mechanism involved in Hsp70 release is controversial because this protein does not present a consensual secretory signal. In this study, we have shown that Hsp70 integrates into artificial lipid bilayer openings of ion conductance pathways. In addition, this protein was found inserted into the plasma membrane of cells after stress. Hsp70 was released into the extracellular environment in a membraneassociated form, sharing the characteristics of this protein in the plasma membrane. Extracellular membranes containing Hsp70 were at least 260-fold more effective than free recombinant protein in inducing TNF-alpha production as an indicator of macrophage activation. These observations suggest that Hsp70 translocates into the plasma membrane after stress and is released within membranous structures from intact cells, which could act as a danger signal to activate the immune system.NIGMS NIH HHS [GM 50878
Imaging of Hsp70-positive tumors with cmHsp70.1 antibody-conjugated gold nanoparticles
No full textMathias K Gehrmann,1 Melanie A Kimm,2 Stefan Stangl,1 Thomas E Schmid,1 Peter B Noël,2 Ernst J Rummeny,2 Gabriele Multhoff11Department of Radiation Oncology, 2Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, GermanyAbstract: Real-time imaging of small tumors is still one of the challenges in cancer diagnosis, prognosis, and monitoring of clinical outcome. Targeting novel biomarkers that are selectively expressed on a large variety of different tumors but not normal cells has the potential to improve the imaging capacity of existing methods such as computed tomography. Herein, we present a novel technique using cmHsp70.1 monoclonal antibody-conjugated spherical gold nanoparticles for quantification of the targeted uptake of gold nanoparticles into membrane Hsp70-positive tumor cells. Upon binding, cmHsp70.1-conjugated gold nanoparticles but not nanoparticles coupled to an isotype-matched IgG1 antibody or empty nanoparticles are rapidly taken up by highly malignant Hsp70 membrane-positive mouse tumor cells. After 24 hours, the cmHsp70.1-conjugated gold nanoparticles are found to be enriched in the perinuclear region. Specificity for membrane Hsp70 was shown by using an Hsp70 knockout tumor cell system. Toxic side effects of the cmHsp70.1-conjugated nanoparticles are not observed at a concentration of 1–10 µg/mL. Experiments are ongoing to evaluate whether cmHsp70.1 antibody-conjugated gold nanoparticles are suitable for the detection of membrane-Hsp70-positive tumors in vivo.Keywords: heat shock protein 70, tumor biomarker, theranostics, multimodal CT, multispectral CT, k-edg
In vivo imaging of CT26 mouse tumours by using cmHsp70.1 monoclonal antibody.
No full textThe major stress-inducible heat shock protein 70 (Hsp70) is frequently present on the cell surface of human tumors, but not on normal cells. Herein, the binding characteristics of the cmHsp70.1 mouse monoclonal antibody (mAb) were evaluated in vitro and in a syngeneic tumor mouse model. More than 50% of the CT26 mouse colon carcinoma cells express Hsp70 on their cell surface at 4 degrees C. After a temperature shift to 37 degrees C, the cmHsp70.1-FITC mAb translocates into early endosomes and lysosomes Intraoperative and near-infrared fluorescence (NIRF) imaging revealed an enrichment of Cy5.5-conjugated mAb cmHsp70.1, but not an identically labelled IgG1 isotype-matched control, in i.p. and s.c. located CT26 tumors, as soon as 30min after i.v. injection into the tail vein. Due to the rapid turnover rate of membrane-bound Hsp70, the fluorescence-labelled cmHsp70.1 mAb became endocytosed and accumulated in the tumor, reaching a maximum after 24h and remained detectable at least up to 96h after a single i.v. injection. The tumor-selective internalization of mAb cmHsp70.1 at the physiological temperature of 37 degrees C might enable a targeted uptake of toxins or radionuclides into Hsp70 membrane-positive tumors. The anti-tumoral activity of the cmHsp70.1 mAb is further supported by its capacity to mediate antibody dependent cytotoxicity (ADCC)
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