Murine alpha-2-macroglobulin increase during inflammatory responses and tumor growth

Objective and Design: To determine the alpha-2-macroglobulin (alpha2M) levels in mice during acute and chronic inflammatory responses. Materials and Methods: Inflammation was induced by one of the following stimuli: carrageenin, zymosan, lipopolysacharide, thioglycollate, bacilli Calmette Guerin, PPD (in pre-immunized and non-immunized animals) and tumor cells. The concentration of alpha2M was determined in plasma or peritoneal liquid by electroimmunoassay. Results: In all the treatments employed, the plasma levels of alpha2M were higher than in untreated animals. This increase varied from 9%, 24 h after injection up a maximum of 66% 72 h post-injection. When compared to animals injected only with saline, the increases were significant 48 h after treatment with either zymosan or LPS, and 72 h after treatment with either thioglycollate or carrageenin. Treatment with BCG triggers an increase in alpha2M levels after 24 h (18.60%) and 48 h (27.90%). Immunized mice presented higher levels of this protein than non-immunized animals after challenge with PPD. The growth of Ehrlich tumor cells in the peritoneal cavity was directly correlated with the local levels of alpha2M which increased 3.5 fold, 10 days after injection. Conclusions: These results strongly indicate that in mice, the concentration of alpha2M can increase during acute and chronic inflammatory reactions with kinetics dependent on the particular kind of inflammatory agent.

Basic ingredients for mathematical modeling of tumor growth in vitro: Cooperative effects and search for space

Based on the literature data from HT-29 cell monolayers, we develop a model for its growth, analogous to an epidemic model, mixing local and global interactions. First, we propose and solve a deterministic equation for the progress of these colonies. Thus, we add a stochastic (local) interaction and simulate the evolution of an Eden-like aggregate by using dynamical Monte Carlo methods. The growth curves of both deterministic and stochastic models are in excellent agreement with the experimental observations. The waiting times distributions, generated via our stochastic model, allowed us to analyze the role of mesoscopic events. We obtain log-normal distributions in the initial stages of the growth and Gaussians at long times. We interpret these outcomes in the light of cellular division events: in the early stages, the phenomena are dependent each other in a multiplicative geometric-based process, and they are independent at long times. We conclude that the main ingredients for a good minimalist model of tumor growth, at mesoscopic level, are intrinsic cooperative mechanisms and competitive search for space. © 2013 Elsevier Ltd.

Effect of treatment with l-amino oxidase fractions, from Bothrops jararaca venom on Ehrlich ascites tumor growth

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Twelve-month clinical outcomes after coronary stenting with the Genous Bio-engineered R Stent in patients with a bifurcation lesion: from the e-HEALING (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth) registry

Background The e-Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth (e-HEALING) registry was designed to capture clinical data on the use of the endothelial progenitor cell capture stent (ECS) in routine clinical practice. In this analysis, we investigated the 12-month clinical outcomes in patients treated with an ECS for a bifurcation lesion. Methods The worldwide, prospective, nonrandomized e-HEALING registry aimed to enrol 5000 patients treated for coronary artery disease with one or more ECS between October 2005 and October 2007. Clinical follow-up was obtained at 1, 6, and 12 months. The primary endpoint was target vessel failure (TVF), defined as the composite of cardiac death, myocardial infarction, and target vessel revascularization at 12 months. Results A total of 573 patients were treated for at least one bifurcation lesion and were assessed in the current analysis. Baseline characteristics showed a median age of 65 years; 21% were diabetic patients and 36% had unstable angina. A total of 63% of the bifurcation lesions were located in the left artery descending and the mean stent length was 20.7 +/- 12.6 mm. At 12 months, TVF was 12.7% and target lesion revascularization was 7.5%. Definite or probable stent thrombosis occurred in 1.7% of the patients. Moreover, one or more stents per lesion [hazard ratio (HR): 2.79, 95% confidence interval (CI): 1.60-4.86, P < 0.001], predilatation (HR: 0.39, 95% CI: 0.17-0.87, P = 0.023), and lesions located in the right coronary artery (HR: 4.56, 95% CI: 1.07-19.5, P = 0.041) were independent predictors of TVF. Conclusion In the e-HEALING registry, coronary bifurcation stenting with the ECS results in favorable clinical outcomes and low incidences of repeat revascularization and stent thrombosis. Coron Artery Dis 23:201-207 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Fish Oil Supplementation Reduces Cachexia and Tumor Growth While Improving Renal Function in Tumor-Bearing Rats

The objective of the present work was to study the renal function of healthy and tumor-bearing rats chronically supplemented with fish oil (FO), a source of n-3 polyunsaturated fatty acids. Weanling male rats were divided in two groups, one control (C) and another orally supplemented for 70 days with FO (1 g/kg body weight). After this time, half the animals of each group were injected in the right flank with a suspension of Walker 256 tumor cells (W and WFO). The W group had less proteinemia reflecting cachectic proteolysis, FO reversed this fact. Tumor weight gain was also reduced in WFO. Glomerular filtration rate (GFR) was not different in FO or W compared to C, but was higher in WFO. Renal plasma flow (RPF) was higher in the FO supplemented groups. The W group had lower plasma osmolality than the C group, but FO supplementation resulted in normalization of this parameter. Fractional sodium excretion (FENa+) of FO rats was similar to C. Proximal Na+ reabsorption, evaluated by lithium clearance, was similar among the groups. Urinary thromboxane B-2 (TXB2) excretion was lower in the supplemented groups. The number of macrophages in renal tissue was higher in W compared to C rats, but was lower in WFO rats compared to W rats. In conclusion, FO supplementation resulted in less tumor growth and cachexia, and appeared to be renoprotective, as suggested by higher RPF and GFR.

Drug-targeting in combined cancer chemotherapy: tumor growth inhibition in mice by association of paclitaxel and etoposide with a cholesterol-rich nanoemulsion

Lipid nanoemulsions (LDE) may be used as carriers of paclitaxel (PTX) and etoposide (ETP) to decrease toxicity and increase the therapeutic action of those drugs. The current study investigates the combined chemotherapy with PTX and ETP associated with LDE. Four groups of 10-20 B16F10 melanoma-bearing mice were treated with LDE-PTX and LDE-ETP in combination (LDE-PTX + ETP), commercial PTX and ETP in combination (PTX + ETP), single LDE-PTX, and single LDE-ETP. PTX and ETX doses were 9 mu mol/kg administered in three intraperitoneal injections on three alternate days. In two control groups mice were treated with saline solution or LDE alone. Tumor growth, metastasis presence, cell-cycle distribution, blood cell counts and histological data were analyzed. Toxicity of all treatments was evaluated in mice without tumors. Tumor growth inhibition was similarly strong in all treatment groups. However, there was a greater reduction in the number of animals bearing metastases in the LDE-PTX + ETP group (30 %) in comparison to the PTX + ETP group (82 %, p < 0.05). Reduction of cellular density, blood vessels and increase of collagen fibers in tumor tissues were observed in the LDE-PTX + ETP group but not in the PTX + ETP group, and in both groups reduced melanoma-related anemia and thrombocytosis were observed. Flow cytometric analysis suggested that LDE-PTX + ETP exhibited greater selectivity to neoplastic cells than PTX-ETP, showing arrest (65 %) in the G(2)/M phase of the cell cycle (p < 0.001). Toxicity manifested by weight loss and myelosuppression was markedly milder in the LDE-PTX + ETP than in the PTX + ETP group. LDE-PTX + ETP combined drug-targeting therapy showed markedly superior anti-cancer properties and reduced toxicity compared to PTX + ETP.

Synthetic phosphoethanolamine a precursor of membrane phospholipids reduce tumor growth in mice bearing melanoma B16-F10 and in vitro induce apoptosis and arrest in G2/M phase

Phosphoethanolamine (Pho-s) is a compound involved in phospholipid turnover, acting as a substrate for many phospholipids of the cell membranes, especially phosphatidylcholine. We recently reported that synthetic Pho-s has potent effects on a wide variety of tumor cells. To determine if Pho-s has a potential antitumor activity, in this study we evaluated the activity of Pho-s against the B16-F10 melanoma both in vitro and in mice bearing a dorsal tumor. The treatment of B16F10 cells with Pho-s resulted in a dose-dependent inhibition of cell proliferation. At low concentrations, this activity appears to be involved in the arrest of the cell cycle at G2/M, while at high concentrations Pho-s induces apoptosis. In accordance with these results, the loss of mitochondrial potential and increased caspase-3 activity suggest that Phos has dual antitumor effects; i.e. it induces apoptosis at high concentrations and modulates the cell cycle at lower concentrations. In vivo, we evaluated the effect of Pho-s in mice bearing B16-F10 melanoma. The results show that Pho-s reduces the tumoral volume increasing survival rate. Furthermore, the tumor doubling time and tumor delays were substantially reduced when compared with untreated mice. Histological analyses reveal that Pho-s induces changes in cell morphology, typical characteristics of apoptosis, in addition the large areas of necrosis correlating with a reduction of tumor size. The results presented here support the hypothesis that Pho-s has antitumor effects by the induction of apoptosis as well as the inhibition of cell proliferation by arrest at G2/M. Thus, Pho-s can be regarded as a promising agent for the treatment of melanoma. Published by Elsevier Masson SAS.

Applying the National Institute for Clinical Excellence criteria to patients treated with the Genous (TM) Bio-engineered R stent (TM): a sub-study of the e-HEALING (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth) worldwide registry

The National Institute for Clinical Excellence (NICE) guidelines recommend the use of bare-metal stents (BMS) in non-complex lesions with a low risk of restenosis (diameter a parts per thousand yen3 mm and lesion length a parts per thousand currency sign15 mm) and the use of drug-eluting stents (DES) in more complex lesions with a high risk of restenosis (diameter < 3.0 mm or lesion length > 15 mm). However, the guidelines were created based on studies evaluating BMS and DES only. We performed an analysis of patients undergoing non-urgent percutaneous coronary intervention with the novel endothelial cell capturing stent (ECS). The ECS is coated with CD34(+) antibodies that attract circulating endothelial progenitor cells to the stent surface, thereby accelerating the endothelialization of the stented area. We analyzed all patients enrolled in the worldwide e-HEALING registry that met the NICE criteria for either low-risk or high-risk lesions and were treated with a parts per thousand yen1 ECS. The main study outcome was target vessel failure (TVF) at 12-month follow-up, defined as the composite of cardiac death or MI and target vessel revascularization (TVR). A total of 4,241 patients were assessed in the current analysis. At 12-month follow-up, TVF occurred in 7.0% of the patients with low-risk lesions and in 8.8% of the patients with high-risk lesions (p = 0.045). When evaluating the diabetic patients versus the non-diabetic patients per risk group, no significant differences were found in TVF, MI or TVR in either risk group. The ECS shows good clinical outcomes in lesions carrying either a high or a low risk of restenosis according to the NICE guidelines with comparable rates of cardiac death, myocardial infarction, and stent thrombosis. The TVF rate with ECS was slightly higher in patients with high-risk lesions, driven by higher clinically driven TLR. The risk of restenosis with ECS in patients carrying high-risk lesions needs to be carefully considered relative to other risks associated with DES. Furthermore, the presence of diabetes mellitus did not influence the incidence of TVF in either risk group.

Interleukin-10 production by tumor infiltrating macrophages plays a role in Human Papillomavirus 16 tumor growth

Abstract Background Human Papillomavirus, HPV, is the main etiological factor for cervical cancer. Different studies show that in women infected with HPV there is a positive correlation between lesion grade and number of infiltrating macrophages, as well as with IL-10 higher expression. Using a HPV16 associated tumor model in mice, TC-1, our laboratory has demonstrated that tumor infiltrating macrophages are M2-like, induce T cell regulatory phenotype and play an important role in tumor growth. M2 macrophages secrete several cytokines, among them IL-10, which has been shown to play a role in T cell suppression by tumor macrophages in other tumor models. In this work, we sought to establish if IL-10 is part of the mechanism by which HPV tumor associated macrophages induce T cell regulatory phenotype, inhibiting anti-tumor activity and facilitating tumor growth. Results TC-1 tumor cells do not express or respond to IL-10, but recruit leukocytes which, within the tumor environment, produce this cytokine. Using IL-10 deficient mice or blocking IL-10 signaling with neutralizing antibodies, we observed a significant reduction in tumor growth, an increase in tumor infiltration by HPV16 E7 specific CD8 lymphocytes, including a population positive for Granzyme B and Perforin expression, and a decrease in the percentage of HPV specific regulatory T cells in the lymph nodes. Conclusions Our data shows that in the HPV16 TC-1 tumor mouse model, IL-10 produced by tumor macrophages induce regulatory phenotype on T cells, an immune escape mechanism that facilitates tumor growth. Our results point to a possible mechanism behind the epidemiologic data that correlates higher IL-10 expression with risk of cervical cancer development in HPV infected women.

Noisy Oncology: applications of bounded noise transitions in modelling tumor growth

I tumori macroscopici e microscopici, dopo la loro prima fase di crescita, sono composti da un numero medio elevato di cellule. Così, in assenza di perturbazioni esterne, la loro crescita e i punti di equilibrio possono essere descritti da equazioni differenziali. Tuttavia, il tumore interagisce fortemente col macroambiente che lo circonda e di conseguenza una descrizione del tutto deterministica risulta a volte inappropriata. In questo caso si può considerare l'interazione con fluttuazioni statistiche, causate da disturbi esterni, utilizzando le equazioni differenziali stocastiche (SDE). Questo è vero in modo particolare quando si cerca di modellizzare tumori altamente immunogenici che interagiscono con il sistema immunitario, in quanto la complessità di questa interazione risulta in fenomeni di multistabilità. Così, il rumore può provocare disturbi e indurre transizioni di stato (Noise-Induced-Transitions). E' importante notare che una NIT può avere implicazioni profonde sulla vita di un paziente, dal momento che una transizione da uno stato di equilibrio piccolo, nelle dimensioni del tumore, ad uno stato di equilibrio macroscopico, nella maggior parte dei casi significa il passaggio dalla vita alla morte. Generalmente l'approccio standard è quello di modellizzare le fluttuazioni stocastiche dei parametri per mezzo di rumore gaussiano bianco o colorato. In alcuni casi però questa procedura è altamente inadeguata, a causa della illimitatezza intrinseca dei rumori gaussiani che può portare a gravi incongruenze biologiche: pertanto devono essere utilizzati dei rumori "limitati", che, tuttavia, sono molto meno studiati di quelli gaussiani. Inoltre, l'insorgenza di NIT dipende dal tipo di rumore scelto, che rivela un nuovo livello di complessità in biologia. Lo scopo di questa tesi è quello di studiare le applicazioni di due tipi diversi di "rumori limitati" nelle transizioni indotte in due casi: interazione tra tumore e sistema immunitario e chemioterapia dei tumori. Nel primo caso, abbiamo anche introdotto un nuovo modello matematico di terapia, che estende, in modo nuovo, il noto modello di Norton-Simon.

Atlas-Based Segmentation of Brain Tumor Images Using a Markov Random Field-Based Tumor Growth Model and Non-Rigid Registration

We propose a new and clinically oriented approach to perform atlas-based segmentation of brain tumor images. A mesh-free method is used to model tumor-induced soft tissue deformations in a healthy brain atlas image with subsequent registration of the modified atlas to a pathologic patient image. The atlas is seeded with a tumor position prior and tumor growth simulating the tumor mass effect is performed with the aim of improving the registration accuracy in case of patients with space-occupying lesions. We perform tests on 2D axial slices of five different patient data sets and show that the approach gives good results for the segmentation of white matter, grey matter, cerebrospinal fluid and the tumor.