Genomics and proteomics approaches to the study of cancer-stroma interactions

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

Analysis of CDKN1A polymorphisms: markers of cancer susceptibility?

The CDKN1A (TP21)(2) gene encodes a 21-kD protein that is a critical downstream mediator of wild-type TP53 and an important regulator of the cell cycle. Failure in the function of this gene would be expected to result in abnormal cell proliferation and transformation. Tumor-associated mutations of the coding region of the TP21 are rare. on the other hand, some TP21 polymorphisms have been identified and characterized by single base substitutions. In the present study, we investigated the potential role of TP21 gene polymorphisms in skin, head, and neck tumorigenesis. A total of 261 samples were examined by polymerase chain reaction single-strand conformational analysis, and one mutation at codon 31 and four polymorphisms in exons 2 (codon 55) and 3 [nucleotide (nt)590] and in promoter region (nt2298) were identified. In conclusion, this investigation confirmed the rarity of mutations in this gene, arguing against a role for TP21 mutations in skin, head, and neck cancers. Also, our results show significant differences in nt2298 allele frequencies between normal individuals and skin malignant tumors (P < 0.05). The results suggest that this polymorphism affects TP21 transactivator binding and may be important during the pathogenesis of skin cancer. (C) 2003 Elsevier B.V. All rights reserved.

Peripheral kappa and delta opioid receptors are involved in the antinociceptive effect of crotalphine in a rat model of cancer pain

Cancer pain is an important clinical problem and may not respond satisfactorily to the current analgesic therapy. We have characterized a novel and potent analgesic peptide, crotalphine, from the venom of the South American rattlesnake Crotalus durissus terrificus. In the present work, the antinociceptive effect of crotalphine was evaluated in a rat model of cancer pain induced by intraplantar injection of Walker 256 carcinoma cells. Intraplantar injection of tumor cells caused the development of hyperalgesia and allodynia, detected on day 5 after tumor cell inoculation. Crotalphine (6 μg/kg), administered p.o., blocked both phenomena. The antinociceptive effect was detected 1 h after treatment and lasted for up to 48 h. Intraplantar injection of nor-binaltorphimine (50 g/paw), a selective antagonist of κ-opioid receptors, antagonized the antinociceptive effect of the peptide, whereas N,N-diallyl-Tyr-Aib-Phe-Leu (ICI 174,864, 10 μg/paw), a selective antagonist of δ-opioid receptors, partially reversed this effect. On the other hand, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP, 20 g/paw), an antagonist of μ-opioid receptors, did not modify crotalphine-induced antinociception. These data indicate that crotalphine induces a potent and long lasting opioid-mediated antinociception in cancer pain. © 2013 Elsevier Inc.

The seasonal and ovarian status effects on in vitro production of domestic cat embryos between Equator and Tropic of Capricorn

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

Brief Report: The lincRNA Hotair Is Required for Epithelial-to-Mesenchymal Transition and Stemness Maintenance of Cancer Cell Lines

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

Prevalence of the germline TP53 p.R337H mutation in families with multiple cases of cancer

Germline mutations in TP53 gene are associated with Li-Fraumeni syndrome (LFS) and its variants Li-Fraumeni-like (LFL). They predispose carriers to a wide variety of early onset tumors. In Brazil, there is a high frequency of a germline mutation in this gene (NC_000017.9: c.1010G>A; p.R337H) in Southern and Southeastern regions, due to a founder effect. It is estimated to be present in 0,3% ofthe local population, but only few families have been detected. Due to this significant divergence, the purpose of this study was to verify the effectiveness of wider criteria for detection of these individuals. Herein, clinical criteria were established, DNA samples were collected, analyzed by Restriction Fragment Length Polymorphism (RFLP) and sequenced. Thus, assessing the prevalence of this mutation in families with multiple cases of cancer. Based on our proposed criteria, one out of 31 patients (3,22%) was found to carry p.R337H mutation. The patient developed ductal invasive breast cancer at age 47, invasive adenocarcinoma of the lung at age 48 and soft-tissue sarcoma at age 49. In addition, an extensive cancer family history was referred, atypical for LFS, including a case of Ewing’s sarcoma. These outcomes indicate that the proposed criteria may detect probable carriers who did not fit previous LFS criteria. Nevertheless, additional studies, which might include a larger number of families and more stringent parameters, will be useful to improve screening sensibility

Nanoparticles increase the efficacy of cancer chemopreventive agents in cells exposed to cigarette smoke condensate

Lung cancer is a leading cause of death in developed countries. Although smoking cessation is a primary strategy for preventing lung cancer, former smokers remain at high risk of cancer. Accordingly, there is a need to increase the efficacy of lung cancer prevention. Poor bioavailability is the main factor limiting the efficacy of chemopreventive agents. The aim of this study was to increase the efficacy of cancer chemopreventive agents by using lipid nanoparticles (NPs) as a carrier. This study evaluated the ability of lipid NPs to modify the pharmacodynamics of chemopreventive agents including N-acetyl-L-cysteine, phenethyl isothiocyanate and resveratrol (RES). The chemopreventive efficacy of these drugs was determined by evaluating their abilities to counteract cytotoxic damage (DNA fragmentation) induced by cigarette smoke condensate (CSC) and to activate protective apoptosis (annexin-V cytofluorimetric staining) in bronchial epithelial cells both in vitro and in ex vivo experiment in mice. NPs decreased the toxicity of RES and increased its ability to counteract CSC cytotoxicity. NPs significantly increased the ability of phenethyl isothiocyanate to attenuate CSC-induced DNA fragmentation at the highest tested dose. In contrast, this potentiating effect was observed at all tested doses of RES, NPs dramatically increasing RES-induced apoptosis in CSC-treated cells. These results provide evidence that NPs are highly effective at increasing the efficacy of lipophilic drugs (RES) but are not effective towards hydrophilic agents (N-acetyl-L-cysteine), which already possess remarkable bioavailability. Intermediate effects were observed for phenethyl isothiocyanate. These findings are relevant to the identification of cancer chemopreventive agents that would benefit from lipid NP delivery.

Genomic alterations in patients showing multiple primary tumors and family history of cancer

Multiple primary tumors (MPT) are a major cause of mortality and morbidity among patients that have survived after the treatment of a first cancer. It has been proposed that after the first primary tumor, high risk of a subsequent tumor could be associated with radiotherapy used as treatment for the first cancer. Other potential risk factors include unhealthy lifestyle, genetic predisposition, aging, environmental determinants or an interaction between these factors. However, an association between the presence of MPT and family history of cancer in cases without clinical and molecular evidence of a known hereditary cancer syndrome is rarely described. Genomic DNA from 12 patients with at least two primary tumors and without mutations on TP53 was evaluated by CytoScan HD Array (Affymetrix). Chromosome Analysis Suite (ChAS) software v.2.0.1 was used considering at least 50 markers for gains; 25 for losses and a minimum of 5Mb for cnLOHs. Data from 1038 phenotypically healthy individuals (Affymetrix) and from Database of Genomic Variants were used as reference. Only alterations found in <1% (rare) or never described (new rare) in the reference population were considered. All cases, except one, presented a family history of cancer. Five cases developed MTP after radiotherapy and only one was located in the same treated area. It was detected 67 rare and 15 new rare genomic alterations encompassing 5.906 genes: 17 losses, 29 gains, and 36 cnLOH. X chromosome presented the higher number of alterations. Two patients with breast cancer presented a large deletion/cnLOH on 7q21. Enrichment analysis revealed 1275 genes associated with breast cancer (p= 0.001), which was diagnosed in 6 patients and their family members (all negative for BRCA1/2 or TP53 mutations). cnLOHs accounted for 44% of all the alterations. A significant proportion of cases (11/12) presented family history of cancer and the patients were not submitted to radiotherapy (7/12). We demonstrated the presence of rare genomic alterations in patients with MPT suggesting their involvement in the MPT development. cnLOH may arise as a new mechanism associated with the risk to develop MPT. All authors have declared no conflicts of interest.

Modeling spatial distribution of cancer incidence in Cordoba, Argentina

Background: Cancer is the second leading cause of death in Argentina, and there is little knowledge about its incidence. The first study based on population-based cancer registry described spatial incidence and indicated that there existed at least county-level aggregation. The aim of the present work is to model the incidence patterns for the most incidence cancer in Córdoba Province, Argentina, using information from the Córdoba Cancer Registry by performing multilevel mixed model approach to deal with dependence and unobserved heterogeneity coming from the geo-reference cancer occurrence. Methods: Standardized incidence rates (world standard population) (SIR) by sex based on 5-year age groups were calculated for 109 districts nested on 26 counties for the most incidence cancers in Cordoba using 2004 database. A Poisson twolevel random effect model representing unobserved heterogeneity between first level-districts and second level-counties was fitted to assess the spatial distribution of the overall and site specific cancer incidence rates. Results: SIR cancer at Córdoba province shown an average of 263.53±138.34 and 200.45±98.30 for men and women, respectively. Considering the ratio site specific mean SIR to the total mean, breast cancer ratio was 0.25±0.19, prostate cancer ratio was 0.12±0.10 and lower values for lung and colon cancer for both sexes. The Poisson two-level random intercepts model fitted for SIR data distributed with overdispersion shown significant hierarchical structure for the cancer incidence distribution. Conclusions: a strong spatial-nested effect for the cancer incidence in Córdoba was observed and will help to begin the study of the factors associated with it.

Variação nômade: Henry Miller, filosofia e o combate contra o juízo

We discuss Henry Miller's novel Tropic of Cancer based on the concept of nomadism, as coined by Deleuze and Guattari. The relation between philosophy and literature is very productive for both. A phenomenon of dual capture between these two areas that is characteristic of a nomadic thinking: literature that engenders philosophy which, in turn, engenders literature, establishing connections, new relations between terms in a distinct nomad variation that dismisses the classical image of thought of its eminence: a perspective between philosophy and literature as form of discussing the nomadism in Miller's novel. Thus, the linkage between philosophy and literature aims to capture the Millerian paths on this new space of thought, which is achieved by giving up any origin, human or divine, and stands as productive thought that affirms the real in a combat waged against the faculty of judgment, or simply of Judgment, in all its forms.

Uma reapresentação de Henry Miller: do período francês à virada mística (1930-1940)

Pós-graduação em Estudos Literários - FCLAR

Dose-dependent effect of Resveratrol on bladder cancer cells: Chemoprevention and oxidative stress

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

Evaluating the links between intake of milk/dairy products and cancer

Milk and dairy products are widely recommended as part of a healthy diet. These products, however, can contain hormones such as insulin-like growth factor 1, and some studies have suggested that a high intake of milk and dairy products may increase the risk of cancer. This review examines recent studies on this topic, with the evidence suggesting that the recommended intake of milk and dairy products (3 servings/day) is safe and, importantly, does not seem to increase the risk of cancer. on the basis of the studies included in this review, cultured milk, yogurt, and low-fat dairy products should be preferred as the milk and dairy products of choice.