145 research outputs found
In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi- or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS61K in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation
On all possible static spherically symmetric EYM solitons and black holes
We prove local existence and uniqueness of static spherically symmetric
solutions of the Einstein-Yang-Mills equations for any action of the rotation
group (or SU(2)) by automorphisms of a principal bundle over space-time whose
structure group is a compact semisimple Lie group G. These actions are
characterized by a vector in the Cartan subalgebra of g and are called regular
if the vector lies in the interior of a Weyl chamber. In the irregular cases
(the majority for larger gauge groups) the boundary value problem that results
for possible asymptotically flat soliton or black hole solutions is more
complicated than in the previously discussed regular cases. In particular,
there is no longer a gauge choice possible in general so that the Yang-Mills
potential can be given by just real-valued functions. We prove the local
existence of regular solutions near the singularities of the system at the
center, the black hole horizon, and at infinity, establish the parameters that
characterize these local solutions, and discuss the set of possible actions and
the numerical methods necessary to search for global solutions. That some
special global solutions exist is easily derived from the fact that su(2) is a
subalgebra of any compact semisimple Lie algebra. But the set of less trivial
global solutions remains to be explored.Comment: 26 pages, 2 figures, LaTeX, misprints corrected, 1 reference adde
Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG
Background: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. Patients and methods: DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). Results: At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44− haplotype survive significantly longer than patients with a Karnofsky index <100 (P = 0.007 versus P = 0.057 in the DTIC-arm) or other HLA haplotypes (P = 0.04 versus P = 0.57 in DTIC-treated patients). Conclusions: DC vaccination could not be demonstrated to be more effective than DTIC chemotherapy in stage IV melanoma patients. The observed association of overall performance status and HLA haplotype with overall survival for patients treated by DC vaccination should be tested in future trials employing DC vaccine
Temozolomide plus pegylated interferon alfa-2b as first-line treatment for stage IV melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG)
Background: Combination of temozolomide (TMZ) with nonpegylated interferon alfa is associated with increased efficacy in terms of response rates compared with monotherapy. A multicenter phase II study was carried out to assess the activity and toxicity of TMZ plus pegylated interferon alfa-2b (peg-IFNα-2b), hypothesizing improved efficacy due to modified pharmacokinetic properties of the novel interferon (IFN) formulation. Patients and methods: In all, 124 patients with stage IV melanoma without prior chemotherapy and no cerebral metastases were treated with 100 μg peg-IFNα-2b s.c. per week and oral TMZ 200 mg/m2 (days 1-5, every 28 days). Primary study end point was objective response, and secondary end points were overall and progression-free survival (PFS) and safety. Results: In all, 116 patients were assessable for response: 2 (1.7%) had a complete response and 19 (16.4%) a partial response (overall response rate 18.1%). Of total, 25.0% achieved disease stabilization and 56.9% progressed. Overall survival was 9.4 months; PFS was 2.8 months. Grade 3/4 thrombocytopenia occurred in 20.7% and grade 3/4 leukopenia in 23.3%. Conclusions: The efficacy of TMZ plus peg-IFNα-2b in this large phase II study is moderate and comparable to published results of the combination of TMZ with non-peg-IFN. Likewise, the safety profile of peg-IFNα-2b seems to be similar to non-peg-IFN when combined with TM
Geometric K-Homology of Flat D-Branes
We use the Baum-Douglas construction of K-homology to explicitly describe
various aspects of D-branes in Type II superstring theory in the absence of
background supergravity form fields. We rigorously derive various stability
criteria for states of D-branes and show how standard bound state constructions
are naturally realized directly in terms of topological K-cycles. We formulate
the mechanism of flux stabilization in terms of the K-homology of non-trivial
fibre bundles. Along the way we derive a number of new mathematical results in
topological K-homology of independent interest.Comment: 45 pages; v2: References added; v3: Some substantial revision and
corrections, main results unchanged but presentation improved, references
added; to be published in Communications in Mathematical Physic
A handlebody calculus for topology change
We consider certain interesting processes in quantum gravity which involve a
change of spatial topology. We use Morse theory and the machinery of
handlebodies to characterise topology changes as suggested by Sorkin. Our
results support the view that that the pair production of Kaluza-Klein
monopoles and the nucleation of various higher dimensional objects are allowed
transitions with non-zero amplitude.Comment: Latex, 32 pages, 7 figure
Generalized Husimi Functions: Analyticity and Information Content
The analytic properties of a class of generalized Husimi functions are
discussed, with particular reference to the problem of state reconstruction.
The class consists of the subset of Wodkiewicz's operational probability
distributions for which the filter reference state is a squeezed vacuum state.
The fact that the function is analytic means that perfectly precise knowledge
of its values over any small region of phase space provides enough information
to reconstruct the density matrix. If, however, one only has imprecise
knowledge of its values, then the amplification of statistical errors which
occurs when one attempts to carry out the continuation seriously limits the
amount of information which can be extracted. To take account of this fact a
distinction is made between explicate, or experimentally accessible
information, and information which is only present in implicate, experimentally
inaccessible form. It is shown that an explicate description of various aspects
of the system can be found localised on various 2 real dimensional surfaces in
complexified phase space. In particular, the continuation of the function to
the purely imaginary part of complexified phase space provides an explicate
description of the Wigner function.Comment: 16 pages, 2 figures, AMS-latex. Replaced with published versio
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