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Oral squamous cell carcinoma OSCC is a public health problem. The hamster buccal pouch model is ideal for analyzing the development of OSCC. This research analysed the effects of sunitinib tyrosine kinase inhibitor in precancerous lesions induced by 7,dimethylbenz a anthracene DMBA in this model.

Thirty-four male hamsters, divided into six groups: The aspects evaluated were anatomopathological features peribuccal area, paws, nose, and furhistological sections of 11794 hamster buccal pouches qualitatively analyzedepithelium thickness, and the rete ridge density estimated. Sunitinib seems to have important benefits in early stage carcinogenesis and may 1174 useful in chemoprevention. Squamous cell carcinoma of the upper aerodigestive tract has a high risk of primary-treatment failure and death.

Some patients will be at risk for malnutrition, infection [ 3 ], severe depression, or suicide. Globally, with few exceptions, survival rates have not improved for decades [ 14 — 7 ].

Oral squamous cell carcinoma OSCC is caused by DNA mutation, often spontaneous but increased by the exposure to a range of mutagens [ 8 ]—one of them being chemical. The changes in the DNA can progress from a normal keratinocyte to a premalignant or a 208 malignant keratinocyte that is characterized by 208 ability to proliferate in a less-controlled way than normal.

The cells become autonomous and cancer results characterized by invasion through the epithelial basement membrane [ 9 ]. In the initial phase of OSCC, cells may proliferate in a process known as hyperplasia. From hyperplasia, cells can progress to mild dysplasia; then to moderate dysplasia, and later to severe dysplasia; the last phase would be OSCC [ 1 ]. Animal tumor models that closely mimic human oral cancers are very important in elucidating the mechanism of xe transformation and so providing leads to effective chemoprevention.

The HBP is covered by a thin layer of stratified squamous epithelium that is very similar to the floor of the mouth and the ventral surface of the tongue in humans, which is the most common site of human OSCC [ 10 ]. HBP carcinomas are preceded by preneoplastic lesions that are similar to those seen in humans [ 5 ]. The early lesions in the HBP look grossly in vivo much as they do clinically in humans and the carcinomas are microscopically identical to those seen in humans [ 11 ]. Treatment strategies for OSCC are diverse due to the unpredictable behavior of the cancer, local invasion, frequent regional lymph node metastases, and a relative resistance to chemotherapeutic drugs leading to an unpredictable prognosis [ 12 ].

The consensus is that the reversal of precancerous lesions or protection from malignant transformation would have a great impact on the prevention and treatment of OSCC [ 13 ]. Accordingly, rete ridge density estimation is considered a very important sign when grading oral borderline malignancies [ 114 ]. In mouse xenograft models, sunitinib exhibits a wide and potent antitumor activity causing regression, growth arrest, or substantially reducing growth of various tumor cell lines [ 15 ].

Sunitinib interferes in some alterations that in cell physiology collectively dictate malignant growth, such as growth signal autonomy of tumoral cells and sustained angiogenesis [ 17 ].

Thus, the goals of this study were to evaluate qualitatively and quantitatively the effect of sunitinib in precancerous lesions induced by 7,dimethylbenz a anthracene DMBA in the hamster buccal pouch. Additionally, important clinical aspects of these animals were described such as weight gain and the clinical aspects of the peribuccal area, paws, nose, and fur. The experiment was performed using 34 five-week-old male Syrian golden hamsters Mesocricetus auratusobtained from a breeding colony from Universidade Federal de Pelotas, Rio Grande do Sul, Brazil.

The animals were randomly divided into six groups: The experiment was divided in two phases. The first 55 days were the induction phase and the second phase was the treatment sunitinib phase that lasted 4 weeks. During the 55 days of induction, in group C, no product was applied to the right buccal pouch. In A group, acetone was applied using a number 4 marten’s fur brush, 3 times per week, in the right buccal pouch.

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South Jordan, UT was applied 2 times per week in the right buccal pouches of the hamsters. Carbamide peroxide is an important coadjuvant for carcinogenesis in this model [ 2122 ].

The drug treatment protocol and the dose chosen were similar to those used in previous studies made with rodents using sunitinib as cancer treatment. At the end of the induction period 55 daysall animals were weighed to determine 20008 amount of sunitinib that should be used. After that, the animals were weighed weekly and the dilution was recalculated and adjusted every week. The animals were weighed at the beginning and the end of the induction period and weekly during the treatment phase with sunitinib.

Both buccal pouches of all animals were dissected, removed, and postfixed in the same solution used for fixation.

The epithelium thickness and the rete ridge density were measured. The epithelium thickness was estimated dd measuring the distance between the most superficial layer of the epithelium and the basal membrane.

Three equidistant sites were measured in every image. To estimate the rete ridge density, an adaptation of the protocol initially described by Klein-Szanto and 117794 [ 25 ] was performed.

The length ,ei the most superficial epithelium layer was measured and the number of rete ridges in that image was counted [ 26 ]. The number of rete ridges was divided by the length of the epithelium and the result was considered the rete ridge density, expressed by the following unit: Both measurements were performed by two blinded, prestandardized investigators. All statistical procedures were performed using the SPSS As soon as the experiment began, most of the manipulated animals stopped using the right buccal pouch for food storage, preferring the left one.

Soon after, the area started losing fur; the ulceration was leii present but suppuration leo. The animals treated with sunitinib presented the signs typical of patients undergoing treatment with sunitinib [ 16 ], such as cold paws with edema and a yellowish color easily seen on the nose and paws; the urine was also intensely yellow, possibly caused by the drug color.

In the histological examination, the keratin, epithelial, and connective tissue layers were examined. A histological description of every group was made and measurements of the epithelium were registered.

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In all groups, most of the slices examined presented a very thin keratin layer. Epithelium did not increase in thickness and the connective tissue did not show alteration. Digitized images of histological dd of the right hamster buccal pouch, stained with hematoxilin and eosin. Two parameters were lel to determine the presence of precancerous lesions: Different hypotheses could be formulated to elucidate this finding; one possible explanation is that one of the side effects of treatment with sunitinib is weight loss, as described by Bagi et al.

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These weight differences between the results found in the present study and those reported by Bagi are probably due to the different protocols used. To produce the precancerous lesions, we used a protocol that is very similar to other well-described protocols to induce OSCC in HBP [ 13212728 ]. The switch to an angiogenic phenotype in hamster buccal pouch carcinogenic model is a less discrete event that occurs between the third and fifth week after ,ei beginning of the induction protocol [ 11 ].

Somewhere between 6 weeks and 10 weeks [ 132728 ] following dr initiation of the protocol, dysplastic lesions are found [ 1 ]. In this protocol, carbamide peroxide was applied as a promoter. This was the action intended in our study. So DMBA was employed to stimulate the presence of mutant cells and carbamide peroxide to increase the proliferation rate of the cells.

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We also tested if carbamide peroxide alone could promote significant changes in the HBP epithelium group CP. In the first parameter analyzed: Another goal of our study was to evaluate the effects of sunitinib in cells with 17194 genetic alterations, but with no invasive growth [ 29 ]. Knowing that sunitinib targets the angiogenic activity in tumors [ 15182324 ] and that OSCC needs angiogenesis to proliferate and invade connective tissue, we wondered if sunitinib would interfere in the initial process hyperplasia and dysplasia lri OSCC.

The HBP epithelium consists of a thin, regular, keratinized stratified squamous epithelium, the epithelium-connective tissue junction being relatively flat, and rete ridges rarely observed [ 3031 ]. Next to the connective tissue, there is 1174 striated muscle layer mixed with soft connective tissue [ 21 ]. Dd histological characteristic is found in all the control groups Figure 4. Rete ridges are adaptive structures that enlarge the epithelium-connective tissue interface df order to achieve a better anchorage for the epithelium and provide a larger exchange surface for nutritional purposes [ 3233 ].

They are a key feature when grading oral borderline malignancies [ 14 ].

This network is necessary to allow tumor growth. Sunitinib would act 208 this angiogenic area, reducing the number of new vessels or avoiding their formation, making it more difficult for the proliferating cells to find a nutritional source.

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In conclusion, to our knowledge, this study is the first to demonstrate some beneficial effects of sunitinib treatment in an animal model of oral precancerous lesions. The main lwi found were reduction of the precancerous lesion growth and ulceration incidences and reduction, to a normal state, of the rete ridge density. More research should be done, but our study suggests that sunitinib treatment should be considered as one possible alternative for the treatment of oral cancer.

The authors declare that they have no conflict of interests regarding the publication of this paper. National Center for Biotechnology InformationU. Published online Feb Author information Article notes Copyright and License information Disclaimer.

Received Dec 5; Accepted Jan 6. This is an 11794 access article distributed under the Creative Commons Attribution License, which lfi unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC. Materials and Methods 2. Animals The experiment was performed using 34 five-week-old male Syrian golden hamsters Mesocricetus auratusobtained from a breeding colony from Universidade Federal de Pelotas, Rio Grande do Sul, Brazil.

Experimental Design The animals were randomly divided into six 111794 Sunitinib Treatment The drug treatment protocol and the dose chosen were similar to those used in previous studies made with rodents using sunitinib as 208 treatment.

Weight The animals were weighed at the beginning and the end of the induction period and weekly during the treatment phase with sunitinib. Open in a separate window. Clinical Aspects As soon as the experiment began, most of the manipulated animals stopped using the right buccal pouch for food storage, preferring the left one.

Qualitative Histological Analysis In the histological examination, the keratin, epithelial, and connective tissue layers were examined. Precancerous Lesions Two parameters were used to determine the presence of precancerous lesions: Conclusion In conclusion, to our knowledge, this study is the first to demonstrate some beneficial effects of sunitinib treatment in an animal model of oral precancerous lesions.

Conflict of Interests The authors declare that they have no conflict of interests regarding the publication of this paper. World Health Organization Classification of Tumors: Pathology and Genetics of Head and Neck Tumors. Scully C, Porter S. ABC of oral health.