Rigid upper bounds for the angular momentum and centre of mass of non-singular asymptotically anti-de Sitter space-times

We prove upper bounds on angular momentum and centre of mass in terms of the Hamiltonian mass and cosmological constant for non-singular asymptotically anti-de Sitter initial data sets satisfying the dominant energy condition. We work in all space-dimensions larger than or equal to three, and allow a large class of asymptotic backgrounds, with spherical and non-spherical conformal infinities; in the latter case, a spin-structure compatibility condition is imposed. We give a large class of non-trivial examples saturating the inequality. We analyse exhaustively the borderline case in space-time dimension four: for spherical cross-sections of Scri, equality together with completeness occurs only in anti-de Sitter space-time. On the other hand, in the toroidal case, regular non-trivial initial data sets saturating the bound exist.Comment: improvements in the presentation; some statements correcte

Optimal eigenvalue estimate for the Dirac-Witten operator on bounded domains with smooth boundary

Eigenvalue estimate for the Dirac-Witten operator is given on bounded domains (with smooth boundary) of spacelike hypersurfaces satisfying the dominant energy condition, under four natural boundary conditions (MIT, APS, modified APS, and chiral conditions). This result is a generalisation of Friedrich's inequality for the usual Dirac operator. The limiting cases are also investigated.Comment: 2007, 18 pages, submitted 02 June 200

In B-CLL, the codon 72 polymorphic variants of p53 are not related to drug resistance and disease prognosis

BACKGROUND: A common sequence polymorphism at codon 72 of the p53 gene encoding either arginine or proline was recently shown to be functionally relevant for apoptosis induction in vitro. In B-type chronic lymphocytic leukemia (B-CLL), p53 gene mutations occur in a subset of patients and are associated with impaired survival and drug resistance. Here, we address the functional relevance of the codon 72 single nucleotide (SNP) polymorphism for cell death sensitivity following exposure to clinically employed cytotoxic drugs and gamma-irradiation. METHODS: 138 B-CLL samples were analysed by SSCP-PCR and sequencing for single nucleotide polymorphism at codon 72 of the p53 gene. The in vitro cytotoxicity assay (DiSC-assay) was performed with 7 drugs (chlorambucil, mafosfamide, fludarabine phosphate, methylprednisolone, doxorubicin, vincristine) or gamma-irradiation. RESULTS: Of the 138 B-CLL samples, 9 samples were homozygous for proline (Pro/Pro), 78 samples homozygous for arginine (Arg/Arg), and 49 samples heterozygous (Arg/Pro). No differences were found for patient survival and cell death triggered by 7 cytotoxic drugs or gamma-irradiation. CONCLUSION: These data indicate that polymorphic variants of p53 codon 72 are not clinically relevant for apoptosis induction or patient survival in B-CLL

Operating efficiency optimization of a field-oriented-controlled induction machine.

Includes bibliographical references

Assessment of free light chains in the cerebrospinal fluid of patients with lymphomatous meningitis - a pilot study

BACKGROUND: Lymphomatous meningitis (LM) represents a severe complication of malignant lymphomas. While clinical suspicion is raised by symptoms ranging from mild disturbances of sensation to severe pain or impaired consciousness, the definite diagnosis of LM is often difficult to obtain. Since B-cell lymphomas are clonally restricted to express either kappa or lambda immunoglobulin light chain, we hypothesised that analysis of free light chain (FLC) ratios might facilitate the diagnosis of LM. METHODS: Kappa and lambda FLC were measured using a novel nephelometric assay in cerebrospinal fluid (CSF) and serum from 17 patients. 5/17 suffered from LM as demonstrated by cytology, immunocytology, and/or imaging procedures. RESULTS: Measurement of FLC concentrations in CSF was achieved for all 17 patients. FLC levels in CSF were lower than serum FLC levels in samples for the same patient obtained at the same time (p < 0.01). CSF and serum FLC concentrations correlated weakly in all patients irrespective of LM status. Significantly more patients with cytopathologically and immunohistochemically proven LM displayed abnormal kappa/lambda FLC ratios in CSF compared to individuals with no LM (p < 0.01). CONCLUSION: This is the first report demonstrating that a significant proportion of LM patients display an abnormal kappa/lambda FLC ratio in the CSF

Лексическое наполнение современных газет российских немцев как реализация этнической функции языка

The purpose of our study was to determine the expression of the pro-apoptotic BAX protein in relation to the mutational status of BAX and p53 (as transcriptional activator of the BAX gene) in benign and malignant thyroid tissue. In 47 patients with thyroid tumours (14 follicular and 3 papillary carcinomas, 14 adenomas and 16 goitres), the DNA was screened for mutations of BAX (exon 1-6) and p53 (exon 5-8) by single-strand conformation polymorphism polymerase chain reaction (SSCP-PCR). Furthermore, the protein expression of BAX, p53 and p21 (which is also increased transcriptionally by p53) was investigated by immunohistochemistry. Surprisingly, we observed elevated BAX levels in patients with thyroid carcinomas compared with patients with adenomas (unpaired t-test: p<0.05) or with goitres (p<0.02). This is in clear contrast to other carcinomas where BAX is frequently inactivated which correlates to a poor prognosis (Sturm et al., 1999). There were no significant differences of the BAX levels between goitres or the adenomas. In the SSCP-PCR analysis, no BAX mutations were detectable. P53 mutation analysis by SSCP-PCR did not reveal any functional p53 mutations in the patients with carcinomas, adenomas or goitres. Nevertheless, patients with carcinomas showed an overexpression (preferentially cytoplasmic) of p53 protein compared with patients with benign tumours (p<0.05). The absence of p53 mutations suggests that the overexpressed p53 is wild type. This is in line with the expression profile of BAX and p21, which showed a higher protein expression in these p53 positive tumours (p<0.05 in the carcinomas compared with the non-malignant lesions). Consequently, the overexpressed p53 might be a correlate for dysregulation without loss of function. This, in turn, might be a reason for the good outcome of some patients with thyroid cancer

Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis

BACKGROUND: TRAIL (tumor necrosis factor related apoptosis inducing ligand) is an apoptosis inducing ligand with high specificity for malignant cell systems. Combined treatment modalities using TRAIL and cytotoxic drugs revealed highly additive effects in different tumour cell lines. Little is known about the efficacy and underlying mechanistic effects of a combined therapy using TRAIL and ionising radiation in solid tumour cell systems. Additionally, little is known about the effect of TRAIL combined with radiation on normal tissues. METHODS: Tumour cell systems derived from breast- (MDA MB231), lung--(NCI H460) colorectal--(Colo 205, HCT-15) and head and neck cancer (FaDu, SCC-4) were treated with a combination of TRAIL and irradiation using two different time schedules. Normal tissue cultures from breast, prostate, renal and bronchial epithelia, small muscle cells, endothelial cells, hepatocytes and fibroblasts were tested accordingly. Apoptosis was determined by fluorescence microscopy and western blot determination of PARP processing. Upregulation of death receptors was quantified by flow cytometry. RESULTS: The combined treatment of TRAIL with irradiation strongly increased apoptosis induction in all treated tumour cell lines compared to treatment with TRAIL or irradiation alone. The synergistic effect was most prominent after sequential application of TRAIL after irradiation. Upregulation of TRAIL receptor DR5 after irradiation was observed in four of six tumour cell lines but did not correlate to tumour cell sensitisation to TRAIL. TRAIL did not show toxicity in normal tissue cell systems. In addition, pre-irradiation did not sensitise all nine tested human normal tissue cell cultures to TRAIL. CONCLUSIONS: Based on the in vitro data, TRAIL represents a very promising candidate for combination with radiotherapy. Sequential application of ionising radiation followed by TRAIL is associated with an synergistic induction of cell death in a large panel of solid tumour cell lines. However, TRAIL receptor upregulation may not be the sole mechanism by which sensitation to TRAIL after irradiation is induced

Characterization of a novel Hodgkin cell-line, HD-MyZ, HD-Myr, with myelomonocytic features mimicking Hodgkin's disease in severe combined immunodeficient mice

A novel Hodgkin cell line, designated HD-MyZ, was established from the pleural effusion of a 29-yr-old patient with Hodgkin's disease (HD) of nodular sclerosing type. The majority of cells grow adherently and display typical morphological characteristics of Reed-Sternberg (RS) and Hodgkin (H) cells, i.e., large multi- and mononucleated cells with prominent nucleoli. Immunofluorescence analysis revealed a myelomonocytoid immunophenotype (expression of CD13 and CD68, and lack of lymphoid markers). HD-MyZ cells strongly expressed restin, a recently described intermediate filament-associated protein, the expression of which is restricted to H cells, RS cells, and in vitro cultivated peripheral blood monocytes. In addition mRNA expression of c-fms (colony-stimulating factor 1 receptor) could be induced in HD-MyZ cells by phorbol myristate acetate (PMA) stimulation. Southern blot analysis did not detect rearrangement of T cell receptor beta and immunoglobulin H loci, thus demonstrating the lack of lymphoid commitment. HD-MyZ cells were also devoid of Epstein-Barr virus genomes. HD-MyZ cells constitutively express mRNAs for interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-5, IL-6, IL-7, IL-8, IL-10, IL-1 receptor (type I), and IL-6 receptor. Stimulation of cells with PMA increased mRNA expression as well as the secretion of IL-1 beta, IL-6, and IL-8, and induced the de novo expression of IL-8 receptors. Xenotransplantation into severe combined immunodeficient (SCID) mice by intravenous or subcutaneous inoculation led to development of disseminated tumors with infiltrative and destructive growth. In addition lymphadenopathy, pleural effusion, and infiltration of spleen were observed. Morphological and immunological analysis of tumor cells revealed the same features as HD-MyZ cells. This cell line might be an important tool for understanding the pathogenesis and biology of HD. In addition the SCID mice model might prove helpful in developing new therapeutic strategies

Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma

Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy or biologicals including TNF-related apoptosis inducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells toward TRAIL-induced apoptosis, in particular by downregulation of the Bak-inhibitory Bcl 2 family protein Mcl 1. Here, we demonstrate that sorafenib overcomes TRAIL resistance in RCC by a mechanism that does not rely on Mcl 1 downregulation. Instead, sorafenib induces a rapid dissipation of the mitochondrial membrane potential (ΔΨ(m)) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of ΔΨ(m) and ROS production induced by sorafenib are independent of caspase activities and do not depend on the presence of the pro-apoptotic Bcl 2 family proteins Bax or Bak indicating that both events are functionally up-stream of the mitochondrial apoptosis signaling cascade. More intriguingly, we find that it is sorafenib-induced ROS accumulation that enables TRAIL to activate caspase 8 in RCC. This leads to apoptosis that involves activation of an amplification loop via the mitochondrial apoptosis pathway. Thus, our mechanistic data indicate that sorafenib bypasses central resistance mechanisms through a direct induction of ΔΨ(m) breakdown and ROS production. Activation of this pathway might represent a useful strategy to overcome the cell-inherent resistance to cancer therapeutics including TRAIL in multiresistant cancers such as RCC

Blocking of transcription factor E2F/DP by dominant-negative mutants in a normal breast epithelial cell line efficiently inhibits apoptosis and induces tumor growth in scid mice

The transcription factor E2F is regulated during the cell cycle through interactions with the product of the retinoblastoma susceptibility gene and related proteins. It is thought that E2F-mediated gene regulation at the G1/S boundary and during S phase may be one of the rate-limiting steps in cell proliferation. It was reported that in vivo overexpression of E2F-1 in fibroblasts induces S phase entry and leads to apoptosis. This observation suggests that E2F plays a role in both cell cycle regulation and apoptosis. To further understand the role of E2F in cell cycle progression, cell death, and tumor development, we have blocked endogenous E2F activity in HBL-100 cells, derived from nonmalignant human breast epithelium, using dominant-negative mutants under the control of a tetracycline-dependent expression system. We have shown here that induction of dominant-negative mutants led to strong downregulation of transiently transfected E2F-dependent chloramphenicol acetyl transferase reporter constructs and of endogenous c-myc, which has been described as a target gene of the transcription factor E2F/DP. In addition, we have shown that blocking of E2F could efficiently protect from apoptosis induced by serum starvation within a period of 10 d, whereas control cells started to die after 24 h. Surprisingly, blocking of E2F did not alter the rate of proliferation or of DNA synthesis of these cells; this finding indicates that cell-cycle progression could be driven in an E2F-independent manner. In addition, we have been able to show that blocking of endogenous E2F in HBL-100 cells led to rapid induction of tumor growth in severe combined immunodeficiency mice. No tumor growth could be observed in mice that received mock-transfected clones or tetracycline to block expression of the E2F mutant constructs in vivo. Thus, it appears that E2F has a potential tumor-suppressive function under certain circumstances. Furthermore, we provide evidence that dysregulation of apoptosis may be an important step in tumorigenesis