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