Evaluation of prognostic markers for canine mast cell tumors treated with vinblastine and prednisone

<p>Abstract</p> <p>Background</p> <p>Canine cutaneous mast cell tumor (MCT) is a common neoplastic disease associated with a variable biologic behavior. Surgery remains the primary treatment for canine MCT; however, radiation therapy (RT) and chemotherapy are commonly used to treat aggressive MCT. The goals of this study were to evaluate the prognostic utility of histologic grade, <it>c-KIT </it>mutations, KIT staining patterns, and the proliferation markers Ki67 and AgNORs in dogs postoperatively treated with vinblastine and prednisone +/- RT, and to compare the outcome of dogs treated with post-operative chemotherapy +/- RT to that of a prognostically matched group treated with surgery alone. Associations between prognostic markers and survival were evaluated. Disease-free intervals (DFI) and overall survival times (OS) of dogs with similar pretreatment prognostic indices postoperatively treated with chemotherapy were compared to dogs treated with surgery alone.</p> <p>Results</p> <p>Histologic grade 3 MCTs, MCTs with c-<it>KIT </it>mutations, MCTs with increased cytoplasmic KIT, and MCTs with increased Ki67 and AgNOR values were associated with decreased DFI and OS. Dogs with histologic grade 3 MCT had significantly increased DFI and OS when treated with chemotherapy vs. surgery alone. Although not statistically significant due to small sample sizes, MCTs with <it>c-KIT </it>mutations had increased DFI and OS when treated with chemotherapy vs. surgery alone.</p> <p>Conclusion and clinical importance</p> <p>This study confirms the prognostic value of histologic grade, c-<it>KIT </it>mutations, KIT staining patterns, and proliferation analyses for canine MCT. Additionally, the results of this study further define the benefit of postoperative vinblastine and prednisone for histologic grade 3 MCTs.</p

Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

Physics at a 100 TeV pp collider: Higgs and EW symmetry breaking studies

This report summarises the physics opportunities for the study of Higgs bosons and the dynamics of electroweak symmetry breaking at the 100 TeV pp collider.Comment: 187 pages, 94 figures. Chapter 2 of the "Physics at the FCC-hh" Repor

Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations: an overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO)

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included

Hallmark of quantum skipping in energy filtered lensless scanning electron microscopy

We simulate the electronic system of ejected electrons arising when a tip, positioned few 10 amp; 8201;nm away from a surface, is operated in the field emission regime. We find that, by repeated quantum reflections quantum skipping , electrons produced at the nanoscale primary site are able to reach the macroscopic environment surrounding the tip surface region. We observe the hallmark of quantum skipping in an energy filtered experiment that detects the spin of the ejected electron

Physics at a 100 TeV pp collider: beyond the Standard Model phenomena

This report summarises the physics opportunities in the search and study of physics beyond the Standard Model at a 100 TeV pp collider.Comment: 196 pages, 114 figures. Chapter 3 of the "Physics at the FCC-hh" Repor

Spectrum-doubled heavy vector bosons at the LHC

We study a simple effective field theory incorporating six heavy vector bosons together with the standard-model field content. The new particles preserve custodial symmetry as well as an approximate left-right parity symmetry. The enhanced symmetry of the model allows it to satisfy precision electroweak constraints and bounds from Higgs physics in a regime where all the couplings are perturbative and where the amount of fine-tuning is comparable to that in the standard model itself. We find that the model could explain the recently observed excesses in di-boson processes at invariant mass close to 2 TeV from LHC Run 1 for a range of allowed parameter space. The masses of all the particles differ by no more than roughly 10%. In a portion of the allowed parameter space only one of the new particles has a production cross section large enough to be detectable with the energy and luminosity of Run 1, both via its decay to WZ and to Wh, while the others have suppressed production rates. The model can be tested at the higher-energy and higher-luminosity run of the LHC even for an overall scale of the new particles higher than 3 TeV

Exploring holographic Composite Higgs models

Simple Composite Higgs models predict new vector-like fermions not too far from the electroweak scale, yet LHC limits are now sensitive to the TeV scale. Motivated by this tension, we explore the holographic dual of the minimal model, MCHM5, to try and alleviate this tension without increasing the fine-tuning in the Higgs potential. Interestingly, we find that lowering the UV cutoff in the 5D picture allows for heavier top partners and less fine-tuning. In the 4D dual this corresponds to increasing the number of “colours” N , thus increasing the decay constant of the Goldstone Higgs. This is essentially a ‘Little Randall-Sundrum Model’, which are known to reduce some flavour and electroweak constraints. Furthermore, in anticipation of the ongoing efforts at the LHC to put bounds on the top Yukawa, we demonstrate that deviations from the SM can be suppressed or enhanced with respect to what is expected from mere symmetry arguments in 4D. We conclude that the 5D holographic realisation of the MCHM5 with a small UV cutoff is not in tension with the current experimental data

Tumor-targeted delivery of biologically active TRAIL protein

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent inducer of tumor cell apoptosis, but concerns of considerable liver toxicity limit its uses in human cancer therapy. Here, we show that i.v. injected Escherichia coli DH5α (E. coli DH5α) specifically replicates in solid tumors and metastases in live animals. E. coli DH5α does not enter tumor cells and suits for being the vector for soluble TRAIL (sTRAIL), which induces apoptosis by activating cell-surface death receptors. With the high ‘tumor-targeting' nature, we demonstrate that intratumoral (i.t.) and intravenous injection of sTRAIL-expressing E. coli DH5α results in the tumor-targeted release of biologically active molecules, which leads to a dramatic reduction in the tumor growth rate and the prolonged survival of tumor-bearing mice. TRAIL delivery by E. coli DH5α did not cause any detectable toxicity to any organs, suggesting that E. coli DH5α-delivered sTRAIL protein therapy may provide a feasible and effective form of treatment for solid tumors