Publications by authors named "Maria Aparecida Marchesan Rodrigues"

46 Publications

Frequency of Human Papillomavirus Detection in Chagasic Megaesophagus Associated or Not with Esophageal Squamous Cell Carcinoma.

Pathobiology 2021 Oct 12:1-9. Epub 2021 Oct 12.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Background: Chagasic megaesophagus (CM) as well as the presence of human papillomavirus (HPV) has been reported as etiological factors for esophageal squamous cell carcinoma (ESCC).

Objective: We assessed the prevalence of HPV DNA in a series of ESCCs associated or not with CM. Data obtained were further correlated to the pathological and clinical data of affected individuals.

Methods: A retrospective study was performed on 92 formalin-fixed and paraffin-embedded tissues collected from patients referred to 3 different hospitals in São Paulo, Brazil: Barretos Cancer Hospital, Barretos, São Paulo; Federal University of Triângulo Mineiro, Uberaba, Minas Gerais; and São Paulo State University, Botucatu, São Paulo. Cases were divided into 3 groups: (i) 24 patients with CM associated with ESCC (CM/ESCC); (ii) 37 patients with ESCC without CM (ESCC); and (iii) 31 patients with CM without ESCC (CM). Detection of HPV DNA was assessed in all samples by a genotyping assay combining multiplex polymerase chain reaction and bead-based Luminex technology.

Results: We identified a high prevalence of high-risk HPV in patients in the CM group (12/31, 38.8%) and CM/ESCC (8/24, 33.3%), compared to individuals in the ESCC group (6/37, 16.3%). The individuals in the groups with cancer (ESCC and CM/ESCC) had a higher frequency of HPV-16 (4/9, 44.5% and 2/8, 25.0%). The other types of high-risk HPVs detected were HPV-31, 45, 51, 53, 56, 66, and 73. We also observed in some samples HPV coinfection by more than one viral type. Despite the high incidence of HPV, it did not show any association with the patient's clinical-pathological and molecular (TP53 mutation status) characteristics.

Conclusion: This is the first report of the presence of HPV DNA in CM associated with ESCC. HPV infection was more presence in megaesophagus lesions. Further studies are needed to confirm and better understand the role of persistent HPV infection in patients with CM.
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http://dx.doi.org/10.1159/000518697DOI Listing
October 2021

Peutz-Jeghers syndrome: an unusual autopsy finding in pregnancy.

Autops Case Rep 2021 Apr 20;11:e2021279. Epub 2021 Apr 20.

Universidade Estadual Paulista (UNESP), Faculdade de Medicina de Botucatu, Departamento de Patologia, Botucatu, SP, Brasil.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant polyposis entity that often remains undiagnosed. The major problems associated with PJS are acute complications due to (i) polyp-related intestinal obstruction, (ii) intussusception, and (iii) the risk of cancer in the long-term. We report the case of a 32-year-old female who presented at the emergency room with signs of acute abdomen and died during the clinical workup. She had a one-month history of nausea, vomiting, and diarrhea and was pregnant at about 30 weeks. There was no contributing past history except for undergoing small bowel resection in infancy. The postmortem examination revealed multiple arborizing polyps throughout the gastrointestinal tract, chiefly in the small bowel. Intestinal obstruction was found at the proximal jejunum with necrosis, perforation, and peritonitis. Histologically, the polyps were composed of tree branch-like bundles of smooth muscle covered by normal-appearing glandular epithelium, confirming the diagnosis of hamartomatous polyps. No malignant or premalignant lesions were detected in the gastrointestinal tract or other organs. This case was an opportunity to analyze the natural history and the pathological features of the Peutz-Jeghers syndrome in an adult and to investigate the presence of neoplastic lesions associated with this condition.
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http://dx.doi.org/10.4322/acr.2021.279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087392PMC
April 2021

What should be the treatment for intestinal neuronal dysplasia type B? A comparative long-term follow-up study.

J Pediatr Surg 2021 Sep 26;56(9):1611-1617. Epub 2020 Nov 26.

Department of Pathology, Botucatu Medical School, UNESP - São Paulo State University, Botucatu, SP, Brazil.

Purpose: To present the long-term follow-up outcomes of patients with intestinal neuronal dysplasia type B (IND-B) managed either conservatively or surgically.

Methods: We conducted an ambispective, observational, longitudinal, and comparative study. Clinical data were reviewed at the start of treatment. After a minimum period of five years, the patients participated in semi-structured interviews in which the bowel function score (BFS) was applied to assess intestinal function, a proposed intestinal symptom index (ISI) to assess clinical symptoms, and a classification of clinical prognosis to assess treatment success. Comparisons between the two types of treatment were performed by evaluating pre- and post-treatment criteria.

Results: Fifty patients diagnosed with IND-B were included in the study. Thirty-eight patients underwent surgical treatment (26 elective surgical treatment for primary colorectal resection and 12 emergency colostomies for intestinal obstruction or enterocolitis). Twelve patients were managed conservatively. With the exception of the patients who required an emergency operation (n = 12), the two groups were composed of patients with severe constipation who had similar clinical and functional characteristics at the time of IND-B diagnosis. A better clinical response was observed in patients submitted to conservative treatment, with a greater increase in the BFS (16.5 [-4/+18] versus 4 [-15/+17]; p = 0.001), indicating better bowel function and a more pronounced drop in ISI (-6 [-7/-4] versus -4 [-6/+1]; p = 0.015), suggesting fewer symptoms. The percentage of patients who had a successful treatment was higher in the group treated conservatively (72.7% versus 42.3%; p = 0.03).

Conclusion: Conservative management showed better long-term outcomes than surgical management in children with IND-B.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.11.019DOI Listing
September 2021

Are biopsies always necessary in upper and lower gastrointestinal endoscopy in children? A retrospective 10-year analysis.

Eur J Pediatr 2021 Apr 16;180(4):1089-1098. Epub 2020 Oct 16.

Pediatric Surgery and Endoscopy Unit, Botucatu Medical School, UNESP, São Paulo, Brazil.

Little attention has been given to the efficiency and validity of performing routine endoscopic biopsies in normal areas in children. This study aimed to investigate the need to perform routine biopsies in upper gastrointestinal endoscopy (UDE) and colonoscopy in normal areas by comparing macroscopy and histology. It was a 10-year retrospective analysis with the inclusion of 761 UDEs and 177 colonoscopies. Considering all segments, UDEs showed false-positive result rates of 73.11% and false-negative result rates of 14.34%. The histological results modified the initial management in 53.95% of patients. Considering all segments, colonoscopies showed false-positive result rates of 63.64% and false-negative result rates of 30.97%. The histological results modified the initial management in 34.45% of patients.Conclusion: If biopsies were obtained only in abnormal areas, the diagnosis would be lost in 53.95% of the patients in upper endoscopies and 85.7% of the colonoscopies, which justifies routine maintenance of biopsies in macroscopically normal areas in children. What is Known: • Little attention has been given to the efficiency and validity of endoscopic biopsies of normal areas during pediatric exams. • Only a few pediatric studies have correlated macroscopic and histological findings from endoscopic biopsies, and low sensitivity and specificity, as well as poor agreement, were reported. What is New: • Our study confirms the evidence that routine biopsies from macroscopically normal areas during upper and lower digestive endoscopies can lead to histopathological diagnoses and different medical management. • This is the first research on this topic in a Latin population, from a developing country, reassuring the results obtained in previous papers from other countries.
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http://dx.doi.org/10.1007/s00431-020-03838-7DOI Listing
April 2021

Capsaicin lacks tumor-promoting effects during colon carcinogenesis in a rat model induced by 1,2-dimethylhydrazine.

Environ Sci Pollut Res Int 2021 Jan 4;28(2):2457-2467. Epub 2020 Sep 4.

Department of Pathology, Medical School, São Paulo State University (UNESP), Botucatu, SP, Brazil.

Capsaicin (CPS, 8-methyl-N-vanillyl-trans-6-nonenamide), a pungent alkaloid from chili peppers, has contradictory effects in both experimental and human carcinogenesis. Thus, we evaluated the modifying effects of chronic CPS during the promotion and progression stages of rat colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH). Male Wistar rats were given four subcutaneous injections of DMH (40 mg/body weight (b.w.)) twice a week, for 2 weeks. After DMH-induced tumor initiation, the animals were treated with CPS at 5 or 50 mg/kg b.w. by gavage for 24 weeks (three times a week). High-dose CPS reduced both cell proliferation in adjacent "normal-appearing" colonic crypts and the total number of preneoplastic aberrant crypt foci (ACF) but did not change the number of dysplastic ACF or ACF multiplicity. Although the proportion of adenomas was increased, and tubular adenocarcinomas decreased in high-dose CPS, both CPS interventions exerted no effects on total tumor incidence, volume, multiplicity, cell proliferation (Ki-67), and apoptosis (caspase-3). In accordance, high-dose CPS treatment had discrete effects on gene expression in colon tumors, as only 3/94 (3.19%) genes were significantly modified (downregulation of Cebpd and Fasl, and upregulation of Jag1). The findings of the present study show that CPS does not impact on the promotion/progression stages of rat colon carcinogenesis. Therefore, CPS at a high-dose intervention showed to be a safe food ingredient.
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http://dx.doi.org/10.1007/s11356-020-10683-6DOI Listing
January 2021

Adjustments in β-Adrenergic Signaling Contribute to the Amelioration of Cardiac Dysfunction by Exercise Training in Supravalvular Aortic Stenosis.

Cell Physiol Biochem 2020 Jul;54(4):665-681

Department of Internal Medicine, Botucatu Medical School, São Paulo State University, Botucatu, São Paulo, Brazil,

Background/aims: Aortic stenosis-induced chronic pressure overload leads to cardiac dysfunction and congestive heart failure. The pathophysiological mechanisms of the myocardial impairment are multifactorial and include maladaptive β-adrenergic signaling. Exercise training (ET) has been used as a non-pharmacological therapy for heart failure management. The present study tested the hypothesis that exercise training attenuates diastolic dysfunction through β-adrenergic signaling preservation.

Methods: Wistar rats were submitted to ascending aortic stenosis (AS) surgery, and after 18 weeks, a moderate aerobic exercise training protocol was performed for ten weeks.

Results: ET attenuated diastolic dysfunction, evaluated by echocardiogram and isolated papillary muscle (IPM) assay. Also, ET reduced features of heart failure, cross-sectional cardiomyocyte area, and exercise intolerance, assessed by treadmill exercise testing. The β2 adrenergic receptor protein expression was increased in AS rats independently of exercise. Interestingly, ET restored the protein levels of phosphorylated phospholamban at Serine 16 and preserved the β-adrenergic receptor responsiveness as visualized by the lower myocardial compliance decline and time to 50% tension development and relaxation during β-adrenergic stimulation in the IPM than untrained rats. Additionally, AS rats presented higher levels of TNFα and iNOS, which were attenuated by ET.

Conclusion: Moderate ET improves exercise tolerance, reduces heart failure features, and attenuates diastolic dysfunction. In the myocardium, ET decreases the cross-sectional area of the cardiomyocyte and preserves the β-adrenergic responsiveness, which reveals that the adjustments in β-adrenergic signaling contribute to the amelioration of cardiac dysfunction by mild exercise training in aortic stenosis rats.
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http://dx.doi.org/10.33594/000000247DOI Listing
July 2020

Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development.

Toxicol Lett 2020 Sep 6;329:67-79. Epub 2020 May 6.

Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, SP, Brazil. Electronic address:

This study unveiled the early cellular and molecular events induced by 1,2-dimethylhydrazine (DMH) in the colon and liver and their implications on pre- and neoplastic lesion burden in a late timepoint. Male Wistar rats received four DMH injections (40 mg/kg body weight) for 2 weeks and were sacrificed 24 h (short-term study) or 22 (medium-term study) weeks after the last DMH administration. In the short-term study, DMH led to increased leukocyte (comet assay) and colon (H2AX) genotoxicity, enhanced proliferation (Ki-67) and apoptosis (caspase-3) indexes in both liver and colon. Furthermore, the expression of mRNA (Cat, Gsta1, Gsta2, Gpx1, Gstm1, Sod1, Sod2 and Sod3) and the activity of antioxidant agents were diminished in the colon and liver of DMH-induced rats, eliciting an environment of oxidative stress featuring elevated lipid hydroperoxide levels. Apoptosis effectors were upregulated in the liver (Bax, Casp3 and Fas), and developmental genes were downregulated in both colon and liver (Foxa1, Foxa2, Smad2 and Smad4). In the medium-term study, DMH led to a high number of preneoplastic colonic aberrant crypt foci and tumors (adenomas and invasive adenocarcinomas) but few preneoplastic hepatic glutathione S-transferase (GST-P)-positive foci. Our novel gene expression data highlights overlooked mechanisms in the liver (main metabolizing organ) and colon (main target organ) on toxicity and carcinogenesis induced by repeated doses of DMH, as both organs should be considered in further interventions on the initiation stage of colon carcinogenesis.
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http://dx.doi.org/10.1016/j.toxlet.2020.04.009DOI Listing
September 2020

Is breath testing without C-labelled external urea able to detect Helicobacter pylori infection?

Anal Bioanal Chem 2019 Sep 15;411(22):5641-5645. Epub 2019 Jun 15.

Stable Isotope Center, Botucatu Institute of Biosciences (IBB), São Paulo State University (UNESP), Prof Dr Antonio Celso W Zanin, Botucatu, SP, 18618-689, Brazil.

Helicobacter pylori (H. pylori) infection is the main cause of gastric inflammation and peptic ulcer disease. Diagnosis and treatment are important to prevent these outcomes. The diagnosis of H. pylori infection can be performed by non-invasive methods, such as C-urea breath test (C-UBT). As endogenous urea is normally released to body cavities, we sought to investigate the usefulness of UBT without C-labelled external urea to detect H. pylori infection. The analysis was performed in a series of adult patients just before upper gastrointestinal endoscopy and biopsy to investigate dyspeptic symptoms. Breath samples were analyzed using isotope ratio mass spectrometry (IRMS). The natural variation of C and O isotopic abundance in the breath samples was also investigated. The results of the isotopic analysis were compared with the findings of the histopathological evaluation of gastric biopsies, which is the gold standard to detect H. pylori infection. No differences between patients with or without H. pylori infection could be detected by the isotope analysis of breath tests without C-urea. Therefore, our results showed that UBT without C-urea, analyzed by IRMS, was not useful to detect H. pylori infection in the study population.
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http://dx.doi.org/10.1007/s00216-019-01961-5DOI Listing
September 2019

Barium Enema Revisited in the Workup for the Diagnosis of Hirschsprung's Disease.

J Pediatr Gastroenterol Nutr 2019 04;68(4):e62-e66

Department of Radiology, Mega Imagem Clinic, Santos, São Paulo, Brazil.

Objective: To analyse the diagnostic capacity of barium enema (BE) in the diagnostic investigation for Hirschsprung's disease (HD) was analyzed for transition zone (TZ) identification and rectosigmoid index (RSI) ≤1.0 determination.

Patients And Methods: BE images were analyzed retrospectively by 2 examiners and the results were compared with the histopathology of rectal biopsies.

Results: TZ identification and RSI ≤1.0 were assessed separately and combined in 43 patients. Twelve (27.9%) patients had the diagnosis of HD based on rectal biopsies. TZ identification presented better diagnostic capacity for the 2 examiners than RSI ≤1.0. However, interexaminer agreement was higher for RSI ≤1.0 than for TZ identification. The combination of TZ identification and RSI ≤1.0 increased the sensitivity (83.3%-92.3%) and the negative predictive value (90.4%-92.3%).

Conclusion: Therefore, the high diagnostic sensitivity of TZ identification combined to RSI ≤1.0 reinforces the usefulness of these BE parameters in the screening for Hirschsprung's disease.
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http://dx.doi.org/10.1097/MPG.0000000000002242DOI Listing
April 2019

mutations are frequent in esophageal squamous cell carcinoma associated with chagasic megaesophagus and are associated with a worse patient outcome.

Infect Agent Cancer 2018 29;13:43. Epub 2018 Dec 29.

1Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, SP CEP 14784 400 Brazil.

Background: Chronic diseases such as chagasic megaesophagus (secondary to Chagas' disease) have been suggested as etiological factors for esophageal squamous cell carcinoma; however, the molecular mechanisms involved are poorly understood.

Objective: We analyzed hotspot gene mutations in a series of esophageal squamous cell carcinomas associated or not with chagasic megaesophagus, as well as, in chagasic megaesophagus biopsies. We also checked for correlations between the presence of mutations with patients' clinical and pathological features.

Methods: The study included three different groups of patients: i) 23 patients with chagasic megaesophagus associated with esophageal squamous cell carcinoma (CM/ESCC); ii) 38 patients with esophageal squamous cell carcinoma not associated with chagasic megaesophagus (ESCC); and iii) 28 patients with chagasic megaesophagus without esophageal squamous cell carcinoma (CM). hotspot mutations in exons 9 and 20 were evaluated by PCR followed by direct sequencing technique.

Results: mutations were identified in 21.7% (5 out of 23) of CM/ESCC cases, in 10.5% (4 out of 38) of ESCC and in only 3.6% (1 case out of 28) of CM cases. In the CM/ESCC group, mutations were significantly associated with lower survival (mean 5 months), when compared to wild-type patients (mean 2.0 years). No other significant associations were observed between mutations and patients' clinical features or mutation profile.

Conclusion: This is the first report on the presence of mutations in esophageal cancer associated with chagasic megaesophagus. The detection of mutations in benign chagasic megaesophagus lesions suggests their putative role in esophageal squamous cell carcinoma development and opens new opportunities for targeted-therapies for these diseases.
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http://dx.doi.org/10.1186/s13027-018-0216-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311070PMC
December 2018

Presence of microsatellite instability in esophageal squamous cell carcinoma associated with chagasic megaesophagus.

Biomark Med 2018 06 6;12(6):573-582. Epub 2018 Jun 6.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.

Aim: The molecular pathogenesis of esophageal squamous cell carcinoma (ESCC) has been increasingly studied, but there is no report on the role of MSI in ESCC development associated with chagasic megaesophagus (CM).Results/methodology: In four ESCC/CM (4/19) we found microsatellite instability (MSI) alterations (21.1%), being three MSI-L (15.8%) and one MSI-H (5.3%). Four out of 35 ESCC cases showed MSI-L (11.4%) and only one out of 26 CM cases presented MSI-L (3.9%). The MSI-H was observed in an ESCC/CM patient that presents lack of MSH6 immunostaining corroborating deficiency in MMR pathway. Interestingly, the MSI-H ESCC/CM case also presented a deletion the HSP110 poly(T)17 gene.

Discussion/conclusion: Taking together, we concluded that MSI is a rare event in esophageal squamous cell carcinoma, but can be associated with CM.
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http://dx.doi.org/10.2217/bmm-2017-0329DOI Listing
June 2018

Capsaicin reduces genotoxicity, colonic cell proliferation and preneoplastic lesions induced by 1,2-dimethylhydrazine in rats.

Toxicol Appl Pharmacol 2018 01 16;338:93-102. Epub 2017 Nov 16.

Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, 18618-689, Brazil. Electronic address:

Capsaicin (8-Methyl-N-vanillyl-(trans)-6-nonenamide) is the major pungent ingredient found in chili peppers consumed worldwide. Most reports on capsaicin potential carcinogenicity have yielded inconsistent findings. Some studies have shown that capsaicin exerts anti-proliferative and pro-apoptotic effects on different cancer cell lines, while others have reported an association between capsaicin at high doses with mutagenicity and carcinogenicity. Thus, this study aimed at assessing the effects of capsaicin administration on 1,2-dimethyl-hydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. Our results show that capsaicin administration, before and during carcinogen exposure, modified DMH-induced cytotoxicity and genotoxicity, promoting anti-proliferative and pro-apoptotic responses through the expression of the genes involved in apoptosis, cell cycle suppression and cell/tissue differentiation. Furthermore, capsaicin reduced aberrant crypt foci (ACF) number and multiplicity, although there were no differences in tumor incidence and multiplicity among the groups. Taken together, the results suggest that capsaicin may have a preventive effect against DMH-induced colorectal carcinogenesis.
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http://dx.doi.org/10.1016/j.taap.2017.11.008DOI Listing
January 2018

Low Concentration of 5-Fluorouracil Increases the Effectiveness of Tumor RNA to Activate Murine Dendritic Cells.

Cancer Biother Radiopharm 2017 Oct;32(8):302-308

2 Department of Microbiology and Immunology, Institute of Biosciences of Botucatu, São Paulo State University (UNESP) , Botucatu, Brazil .

Aim: Considering the central role of dendritic cells (DCs) on the development of an antitumor immune response, in this study we used a murine model to evaluate how DC transfection with drug-treated tumor cell RNA changes their phenotype, and whether transfection enhances the in vivo effectiveness of a DC-based antitumor vaccine.

Materials And Methods: MC-38 colorectal tumor cells were pretreated with the minimum effective concentration of 5-fluorouracil (5-FU), then their total RNA was extracted and transfected into DCs. These DCs were inoculated into C57Bl/6 mice bearing subcutaneous MC-38 tumor.

Results: DC transfection with drug-treated tumor RNA increases the percentages of CD40 (from 37.6% to 61.4%), CD86 (from 39.8% to 53.4%), and major histocompatibility complex class II (from 51.2% to 75.3%) cells, whereas significantly increases the in vivo generation of interferon-γ producer lymphocytes.

Conclusion: These results reinforce our view that treatment of tumor cells with 5-FU induces transcriptional changes that can be transferred to DCs by RNA transfection, enhancing their ability to stimulate an antitumor response.
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http://dx.doi.org/10.1089/cbr.2017.2259DOI Listing
October 2017

Long-term follow-up of patients with intestinal neuronal dysplasia type B: Protocol for an observational, ambispective, and comparative study.

Medicine (Baltimore) 2017 Jul;96(28):e7485

Discipline of Pediatric Surgery-Department of Surgery and Orthopedics Botucatu Medical School, São Paulo State University (UNESP), São Paulo, Brazil Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), São Paulo, Brazil.

Intestinal neuronal dysplasia type B (IND-B) is a pathological entity of the group of gastrointestinal neuromuscular diseases characterized by complex alterations in the enteric nervous system. Patients typically present with intestinal constipation, sometimes complicated by episodes of intestinal obstruction. The 2 therapeutic modalities include conservative clinical treatment and surgical treatment. Nevertheless, the results of the different therapeutic modalities are conflicting, and follow-up studies are scarce and include only a limited number of patients.This is a single-center, ambispective, observational, longitudinal, and comparative follow-up study to compare the results of conservative clinical and surgical treatments in patients with IND-B. Sixty-three patients (<15 years) who received this diagnosis will be included. These patients will be divided into 2 groups according to the type of treatment that they previously received: 29 patients in the surgical treatment group and 34 patients in the conservative treatment group. Previous data will be recovered from the medical records of the study patients, including signs and symptoms present at the time of diagnosis, particularly those related to bowel habits, and treatments undergone. Later, these patients will be invited to participate in a semistructured interview during which aspects related to the long-term functional results of the bowel habit and quality of life will be investigated after a minimum interval of 5 years posttreatment.This project aims to assess the long-term clinical evolution of patients diagnosed with IND-B and compare the results obtained following conservative clinical and surgical treatments.This protocol will provide sufficient data to analyze the long-term clinical outcome obtained through the 2 treatment modalities proposed for patients with IND-B.
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http://dx.doi.org/10.1097/MD.0000000000007485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515763PMC
July 2017

Intestinal neuronal dysplasia type B: A still little known diagnosis for organic causes of intestinal chronic constipation.

World J Gastrointest Pharmacol Ther 2016 Aug;7(3):397-405

Pedro Luiz Toledo de Arruda Lourenção, Erika Veruska Paiva Ortolan, Department of Surgery and Orthopedics, Botucatu Medical School - Unesp, Botucatu, São Paulo 18618-687, Brazil.

Intestinal neuronal dysplasia type B (IND-B) is a controversial entity among the gastrointestinal neuromuscular disorders. It may occur alone or associated with other neuropathies, such as Hirschsprung's disease (HD). Chronic constipation is the most common clinical manifestation of patients. IND-B primarily affects young children and mimics HD, but has its own histopathologic features characterized mainly by hyperplasia of the submucosal nerve plexus. Thus, IND-B should be included in the differential diagnoses of organic causes of constipation. In recent years, an increasing number of cases of IND-B in adults have also been described, some presenting severe constipation since childhood and others with the onset of symptoms at adulthood. Despite the intense scientific research in the last decades, there are still knowledge gaps regarding definition, pathogenesis, diagnostic criteria and therapeutic possibilities for IND-B. However, in medical practice, we continue to encounter patients with severe constipation or intestinal obstruction who undergo to diagnostic investigation for HD and their rectal biopsies present hyperganglionosis in the submucosal nerve plexus and other features, consistent with the diagnosis of IND-B. This review critically discusses aspects related to the disease definitions, pathophysiology and genetics, epidemiology distribution, clinical presentation, diagnostic criteria and therapeutic possibilities of this still little-known organic cause of intestinal chronic constipation.
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http://dx.doi.org/10.4292/wjgpt.v7.i3.397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986395PMC
August 2016

Fetal developmental programing: insights from human studies and experimental models.

J Matern Fetal Neonatal Med 2017 Mar 23;30(6):722-728. Epub 2016 May 23.

a Department of Pathology , Botucatu Medical School, UNESP - Univ. Estadual Paulista , Botucatu , SP , Brazil.

Background: Environmental factors, particularly nutrition during pregnancy and early life can influence the risk of chronic diseases in later life. The underlying mechanism, termed "programing", postulates that an environmental stimulus during a critical window of time, early in life, has a permanent effect on subsequent structure and function of the organism.

Objective: In this study we review the concept of fetal programing on chronic diseases and the proposed hypotheses for the association between early development and later disease, including epigenetic variation. We concentrate on specific aspects of maternal nutrition, particularly under-nutrition and over-nutrition, in humans and animal models.

Conclusion: An adequate maternal nutrition during pregnancy is crucial for the health outcome of the offspring at adulthood.
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http://dx.doi.org/10.1080/14767058.2016.1183635DOI Listing
March 2017

Early Life and Postnatal Western Diet Feeding and Susceptibility to Chemically Induced Colonic Aberrant Crypt Foci in Male Rats Offspring.

Nutr Cancer 2016 07 13;68(5):811-7. Epub 2016 May 13.

a Department of Pathology , Botucatu Medical School, UNESP - Univ Estadual Paulista , Botucatu , SP , Brazil.

The modifying effects of a Western diet (WD) during early life on the susceptibility to colon carcinogenesis induced by dimethylhydrazine (DMH) were examined in male rats as later adults. Three groups were studied: a lifetime control diet-fed group, a test group fed WD since pregnancy from dams until postnatal day (PND) 42, and a group fed WD at adulthood. At PND 70, all groups received the carcinogen DMH and were euthanized 10 wk later. Colonic aberrant crypt foci (ACF) were scored (number and crypt multiplicity) and the altered pattern of β-catenin expression was evaluated in the colonic lesions. ACF multiplicity (≥4 crypts) was significantly higher in the group fed WD at early life than in the group fed the control diet. ACF number, crypt multiplicity, and the number of high-grade dysplastic lesions were significantly higher in the group fed WD at adulthood than in the groupfed the control diet. The number of lesions with altered β-catenin expression was higher in the groups receiving WD at early life or at adulthood than in the lifetime control-diet-fed group. These findings indicate that WD exposure at early life increased the susceptibility to colon carcinogenesis at adulthood.
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http://dx.doi.org/10.1080/01635581.2016.1170167DOI Listing
July 2016

The Glasgow Prognostic Score. An useful tool to predict survival in patients with advanced esophageal squamous cell carcinoma.

Acta Cir Bras 2015 Aug;30(8):580-5

Department of Pathology, Botucatu Medical School, UNESP, Botucatu, SP, BR.

Purpose: To evaluate the usefulness of the Glasgow Prognostic Score (GPS) in patients with esophageal carcinoma (EC).

Methods: A total of 50 patients with EC were analyzed for GPS, nutritional and clinicopathologic parameters. Patients with CRP ≤ 1.0mg/L and albumin ≥ 3.5mg/L were considered as GPS = 0. Patients with only CRP increased or albumin decreased were classified as GPS = 1 and patients with CRP > 1.0mg/L and albumin < 3.5mg/L were considered as GPS = 2.

Results: GPS of 0, 1 and 2 were observed in seven, 23 and 20 patients, respectively. A significant inverse relationship was observed between GPS scores and the survival rate. The survival rate was greatest in patients with GPS = 0 and significantly higher than those from patients with GPS = 1 and GPS = 2. Minimum 12-month survival was observed in 71% patients with GPS = 0 and in 30% patients with GPS = 1. None of the patients with GPS = 2 survived for 12 months. A significant relationship between CRP or albumin individually and the survival rate was observed. No significant relationship among nutritional, clinic pathological parameters and survival was found.

Conclusion: Glasgow Prognostic Score is an useful tool to predict survival in patients with esophageal carcinoma.
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http://dx.doi.org/10.1590/S0102-8650201500800000010DOI Listing
August 2015

Chondroma of the falx cerebri.

Rev Assoc Med Bras (1992) 2015 Jan-Feb;61(1):17-8

Department of Pathology, Botucatu Medical School, UNESP, São Paulo, SP, Brazil.

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http://dx.doi.org/10.1590/1806-9282.61.01.017DOI Listing
August 2015

Epidemiological features of esophageal cancer. Squamous cell carcinoma versus adenocarcinoma.

Acta Cir Bras 2014 Jun;29(6):389-93

Department of Pathology, Botucatu Medical School, UNESP, Botucatu, SP, Brazil.

Purpose: To analyze the epidemiological features of patients with esophageal cancer according to the histopathological types: squamous cell carcinoma or adenocarcinoma.

Methods: A total of 100 patients with esophageal cancer, being 50 squamous cell carcinomas and 50 adenocarcinomas were analyzed for demographics, nutritional factors, lifestyle habits, benign pathological conditions associated, like Barrett's esophagus and megaesophagus, tumor stage and survival rates. The nutritional factors evaluated included body mass index, percent weight loss, hemoglobin and albumin serum levels.

Results: Esophageal cancer occurred more often in men over 50 years-old in both histological groups. No significant differences on age and gender were found between the histological groups. Squamous cell carcinoma was significantly more frequent in blacks than adenocarcinoma. Alcohol consumption and smoking were significantly associated with squamous cell carcinoma. Higher values of body mass index were seen in patients with adenocarcinoma. Barrett's esophagus was found in nine patients (18%) with adenocarcinoma, and megaesophagus in two patients (4%) with squamous cell carcinoma. The majority of patients were on stages III and IV in both histological groups. The mean survival rates were 7.7 ± 9.5 months for patients with squamous cell carcinoma and 8.0 ± 10.9 months for patients with adenocarcinoma. No significant differences on tumor stage and survival rates were detected between the histological groups.

Conclusion: Epidemiological features are distinct for the histopathological types of esophageal cancer. Squamous cell carcinoma is associated with black race, alcohol and smoking, while adenocarcinoma is related to higher body mass index, white race and Barrett's esophagus.
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http://dx.doi.org/10.1590/s0102-86502014000600007DOI Listing
June 2014

Primary sclerosing cholangitis associated with severe ulcerative colitis in a young man.

Autops Case Rep 2013 Oct-Dec;3(4):37-41. Epub 2013 Dec 31.

Department of Pathology - Faculdade de Medicina - Universidade Estadual Paulista, Botucatu/SP, Brazil.

Primary sclerosing cholangitis, a chronic progressive cholestatic liver disease, is the most serious hepatobiliary complication of ulcerative colitis (UC). The authors present the case of a severe and intractable form of UC associated with primary sclerosing cholangitis, in which the diagnosis of this hepatobiliary complication was made during the postmortem examination. A 19-year-old man, with an 8-month diagnosis of UC, was non-responsive to any therapeutic approach. He presented at the emergency care unit severely ill and with cachexia, and subsequently died of septic shock. The postmortem examination confirmed the clinical diagnosis of severe UC and disclosed the presence of primary sclerosing cholangitis. Although laboratory tests have shown a typical cholestatic profile with elevated alkaline phosphatase and gamma-glutamyl transferase levels, hepatic dysfunction was related to sepsis. This report highlights how challenging the diagnosis of primary sclerosing cholangitis can be and shows the value of the postmortem examination to add important information to a medical diagnosis.
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http://dx.doi.org/10.4322/acr.2013.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453659PMC
December 2013

Late administration of a specific COX-2 inhibitor does not treat and/or prevent progression of gastric tumors in rats submitted to duodenogastric reflux procedure.

Acta Cir Bras 2013 Jun;28(6):453-7

Departament of Surgery and Orthopedics, Faculty of Medicine, UNESP, Botucatu-SP, Brazil.

Purpose: To assess whether late introduction of a specific COX-2 inhibitor (Meloxicam) can treat and/or prevent the progression of tumors in the stomach of rats submitted to duodenogastric reflux.

Methods: Seventy five male Wistar rats, weighing 150 grams, were submitted to the induction of duodenogastric reflux through the pylorus. At 36 weeks of follow-up were established three experimental groups: DGR36 sacrificed immediately, DGR54 and DGR54MLX both sacrificed at 54th week of follow-up . The animals of the latter group were fed with a rat chow premixed with Meloxicam (2.0 mg/ kg feed; 0.3 mg / kg bw / day) and the other two with standard rat chow. The lesions found in the pyloric mucosa and gastrojejunal anastomosis were analyzed macroscopically and histologically. For statistical analysis was adjusted a generalized linear model assuming a binomial distribution with LOGIT link function.

Results: No significant differences were found when comparing the incidences of benign tumor lesions (Adenomatous Hyperplasia), p=0.4915, or malignant (Mucinous Adenocarcinoma), p=0.2731, among groups.

Conclusion: Late introduction of specific COX-2 inhibitor (Meloxicam) did not treat and was not able to prevent the progression of tumoral lesions induced by duodenogastric reflux in the rat stomachs.
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http://dx.doi.org/10.1590/s0102-86502013000600009DOI Listing
June 2013

Outcome of superficial squamous cell carcinoma of the esophagus: a clinicopathological study.

Acta Cir Bras 2013 May;28(5):373-8

Gastroenterology Surgery Division, Department of Surgery, Botucatu Medical School, São Paulo State University, SP, Brazil.

Purpose: To analyze the clinicopathological features and outcome of patients with pathologically proven superficial squamous cell carcinoma of the esophagus.

Methods: A total of 234 consecutive cases of esophageal carcinoma in a 15-year period were reviewed.

Results: Superficial esophageal cancer was found in five patients (2.1%). They were four men and one woman and the mean age was 52.5 years. Smoking and alcohol were the main risk factors. Achalasia due to Chagas disease occurred in one patient and a second primary tumor developed in the larynx in another patient. Four patients underwent esophagectomy and one patient received chemoradiotherapy. The histopathologic diagnosis was of squamous cell carcinoma in all cases. Intramucosal tumor (Tis) was identified in three cases and superficially invasive carcinoma in two cases. Four patients are free of disease with survival times of two, four, six and nine years. The patient who developed laryngeal cancer died six years after esophagectomy.

Conclusion: Long-term survival in patients with esophageal cancer is related to early diagnosis. Therefore, a less aggressive surgical approach, such as endoscopic resection, may be a good option for these patients, if depth of tumor invasion can be accurately predicted by the new imaging tools.
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http://dx.doi.org/10.1590/s0102-86502013000500009DOI Listing
May 2013

A useful panel for the diagnosis of Hirschsprung disease in rectal biopsies: calretinin immunostaining and acetylcholinesterase histochesmistry.

Ann Diagn Pathol 2013 Aug 14;17(4):352-6. Epub 2013 May 14.

Department of Surgery, Division of Pediatric Surgery, Botucatu Medical School, UNESP, Univ Estadual Paulista, Botucatu, SP, Brazil.

The pathological evaluation of rectal biopsies for the diagnosis of Hirschsprung disease has been a challenging issue. We analyzed prospectively the usefulness of calretinin immunostaining and acetylcholinesterase (AChE) histochesmistry in rectal biopsies for the diagnosis of Hirschsprung disease. Frozen tissue samples from 43 patients were used for AChE histochemistry and paraffin-embedded sections for calretinin immunohistochemistry and conventional histology (hematoxylin and eosin [H&E]). Activity for AChE, was demonstrated in 13 of 43 cases, and the absence of immunoreactivity for calretinin was observed in 14 of 43 cases. Conventional histology (H&E) did not reveal ganglion cells in 24 of 43 cases. The results on calretinin were in good agreement with AChE according to the κ index (0.946; P<.001) and presented significantly higher specificity (96.7×63.3; P<.002) and accuracy (97.6×74.4; P<.003) when compared with conventional histology (H&E). The final diagnosis of Hirschsprung disease was confirmed in 13 of 43 patients who were submitted to surgical treatment. The results of the present study indicate that calretinin can be a good tool in ruling out the diagnosis of Hirschsprung disease, by showing positive staining in ganglion cells and intrinsic nerve fibers, whereas AChE is useful in confirming the diagnosis of Hirschsprung disease, by revealing activity of this enzyme in hypertrophied nerve fibers. The association between calretinin and AChE can be a useful panel for the histopathologic evaluation of rectal biopsies for the diagnosis of Hirschsprung disease.
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http://dx.doi.org/10.1016/j.anndiagpath.2013.04.004DOI Listing
August 2013

Lack of protective effects of zinc gluconate against rat colon carcinogenesis.

Nutr Cancer 2013 ;65(4):571-7

Department of Pathology, Botucatu Medical School, UNESP, Sao Paulo State University, Sao Paulo, Brasil.

Zinc has been proposed as a promising chemopreventive candidate against colon cancer. However, few studies on the potential beneficial effects of this trace element on cancer chemoprevention are available. The present study was designed to investigate the potential modifying influence of zinc gluconate (ZnGly) on the initiation step of colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH). Male Wistar rats received orally ZnGly (15 mg elemental zinc/kg, 3 times per wk) 2 wk before and during DMH treatment (3 × 40 mg/kg, once a wk). The animals were euthanized at the end of 4th and 16th wk. Colons were analyzed for aberrant crypt foci (ACF) and tumor development. Blood and colon zinc levels, cell proliferation, and apoptosis indexes in colonic crypts were analyzed 24 h after the last DMH administration. Oral treatment with ZnGly did neither alter the number of ACF nor the indexes of cell proliferation and apoptosis in the colonic mucosa. The incidence and multiplicity of colon tumors induced by DMH and their histopathological patterns were not modified by previous treatment with ZnGly. These findings indicate a lack of chemopreventive action of zinc gluconate supplementation on the initiation step of rat colon carcinogenesis induced by DMH.
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http://dx.doi.org/10.1080/01635581.2013.775317DOI Listing
December 2013

Effects of Ginkgo biloba on chemically-induced mammary tumors in rats receiving tamoxifen.

BMC Complement Altern Med 2013 May 1;13:93. Epub 2013 May 1.

Post-Graduation Program in Pathology, School of Medicine, UNESP - Univ Estadual Paulista, Botucatu, SP 18618-970, Brazil.

Background: Ginkgo biloba extract (GbE) is used extensively by breast cancer patients undergoing treatment with Tamoxifen (TAM). Thus, the present study investigated the effects of GbE in female Sprague-Dawley (SD) rats bearing chemically-induced mammary tumors and receiving TAM.

Methods: Animals bearing mammary tumors (≥1 cm in diameter) were divided into four groups: TAM [10 mg/kg, intragastrically (i.g.)], TAM plus GbE [50 and 100 mg/kg, intraperitoneally (i.p.)] or an untreated control group. After 4 weeks, the therapeutic efficacy of the different treatments was evaluated by measuring the tumor volume (cm(3)) and the proportions of each tumor that were alive, necrotic or degenerative (mm(2)). In addition, labeling indexes (LI%) were calculated for cell proliferation (PCNA LI%) and apoptosis (cleaved caspase-3 LI%), expression of estrogen receptor-alpha (ER-α) and p63 biomarkers.

Results: Overall, the tumor volume and the PCNA LI% within live tumor areas were reduced by 83% and 99%, respectively, in all TAM-treated groups when compared to the untreated control group. GbE treatment (100 mg/kg) reduced the proportions of live (24.8%) and necrotic areas (2.9%) (p = 0.046 and p = 0.038, respectively) and significantly increased the proportion of degenerative areas (72.9%) (p = 0.004) in mammary tumors when compared to the group treated only with TAM. The expression of ER-α, p63 and cleaved caspase-3 in live tumor tissues was not modified by GbE treatment.

Conclusions: Co-treatment with 100 mg/kg GbE presented a slightly beneficial effect on the therapeutic efficacy of TAM in female SD rats bearing mammary tumors.
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http://dx.doi.org/10.1186/1472-6882-13-93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655872PMC
May 2013

Upper gastrointestinal histopathological findings in children and adolescents with nonulcer dyspepsia with Helicobacter pylori infection.

J Pediatr Gastroenterol Nutr 2012 Nov;55(5):523-9

Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Botucatu Medical School, UNESP, Sao Paulo State University, Botucatu, SP, Brazil.

Objectives: The aim of the study was to investigate the histopathological lesions in the upper gastrointestinal mucosa associated with Helicobacter pylori infection in children with nonulcer dyspepsia.

Methods: A cross-sectional case-control study was performed on 185 Brazilian children and adolescents (4-17 years, mean 9.5 ± 2.7 years), 63.2% girls, submitted to upper gastrointestinal endoscopy. The histopathological lesions of the esophageal and gastric mucosa were analyzed in biopsy samples.

Results: H pylori infection was identified in 96 children (51.8%). Moderate to severe chronic active gastritis was present in antrum (70.5%) and corpus (45.2%), with higher grading in antrum than in corpus (P < 0.05). The topographic distribution of inflammation was pangastritis (61.9%), followed by antral (32.1%) and corpus (5.9%). H pylori density was higher in antrum than in corpus. Intestinal metaplasia was not found in the H pylori-infected group, nor was significant gastric atrophy. The scores for esophagitis were significantly higher (P < 0.05) in the noninfected group (1.4 ± 0.8) than in the H pylori-infected group (1.07 ± 0.9), with significant negative correlation (r = 0.29; P < 0.05) with the scores of gastric inflammation.

Conclusions: The prevalence of H pylori infection was high among children with dyspepsia and associated with moderate/severe degrees of gastric inflammation. The high scores of esophagitis in the noninfected group point to 2 distinct groups of pathological conditions sharing similar clinical patterns.
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http://dx.doi.org/10.1097/MPG.0b013e3182618136DOI Listing
November 2012

Diclofenac sodium and Imipenem action on rat intestinal mucosa: a biomechanical and histological study.

Acta Cir Bras 2012 Feb;27(2):131-6

Department of Surgery and Orthopedics, Gastroenterological Surgery, Botucatu Medical School, UNESP, Brazil.

Purpose: To study diclofenac sodium induced histological and mechanical alterations and their prevention with Imipenem in rat intestine.

Methods: Male Wistar rats (n=240) were randomly assigned to four experimental groups: GI: n=60 treated with 0.9% saline IM; GII: n=60 treated with 6 mg/kg body weight diclofenac sodium IM for four days; GIII: n=60 treated with 30 mg/kg body weight Imipenem IM for four days, and GIV n=60 treated with diclofenac sodium plus Imipenem at the above doses IM for 4 days. Each group was further divided into 4 subgroups of 15 rats each and sacrificed at 4, 7, 14, and 21 days of follow-up, respectively. Abdominal cavity macroscopy and histology, and small bowel breaking strength were analyzed at each sacrifice moment.

Results: There were no histological or mechanical alterations in normal control rats throughout the study. Ulcerated lesions in intestinal mucosa were observed and breaking strength decreased in all diclofenac sodium treated rats. Ulcerated lesions in intestinal mucosa were prevented by Imipenem in all rats.

Conclusion: Diclofenac sodium induced ulcerated lesions in rat intestinal mucosa can be prevented by Imipenem treatment.
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http://dx.doi.org/10.1590/s0102-86502012000200006DOI Listing
February 2012

Evaluation of carcinogenic potential of diuron in a rat mammary two-stage carcinogenesis model.

Toxicol Pathol 2011 Apr 11;39(3):486-95. Epub 2011 Mar 11.

Medical School, UNESP-São Paulo State University, Department of Pathology, Botucatu-SP, Brazil.

This study aimed to evaluate the carcinogenic potential of the herbicide Diuron in a two-stage rat medium-term mammary carcinogenesis model initiated by 7,12-dimethylbenz(a)anthracene (DMBA). Female seven-week-old Sprague-Dawley (SD) rats were allocated to six groups: groups G1 to G4 received intragastrically (i.g.) a single 50 mg/kg dose of DMBA; groups G5 and G6 received single administration of canola oil (vehicle of DMBA). Groups G1 and G5 received a basal diet, and groups G2, G3, G4, and G6 were fed the basal diet with the addition of Diuron at 250, 1250, 2500, and 2500 ppm, respectively. After twenty-five weeks, the animals were euthanized and mammary tumors were histologically confirmed and quantified. Tumor samples were also processed for immunohistochemical evaluation of the expressions of proliferating cell nuclear antigen (PCNA), cleaved caspase-3, estrogen receptor-α (ER-α), p63, bcl-2, and bak. Diuron treatment did not increase the incidence or multiplicity of mammary tumors (groups G2 to G4 versus Group G1). Also, exposure to Diuron did not alter tumor growth (cell proliferation and apoptosis indexes) or immunoreactivity to ER-α, p63 (myoephitelial marker), or bcl-2 and bak (apoptosis regulatory proteins). These findings indicate that Diuron does not have a promoting potential on mammary carcinogenesis in female SD rats initiated with DMBA.
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http://dx.doi.org/10.1177/0192623310396904DOI Listing
April 2011
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