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1.
Transplant Proc ; 50(10): 3811-3815, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30501900

ABSTRACT

BACKGROUND: Ischemia-reperfusion injury is an unavoidable aspect of transplantation, as well as an important cause of acute kidney injury in clinical practice. Pre- and post-ischemic conditioning are strategies that may provide organs with resistance to major ischemic events. This study evaluates the effects of ischemic preconditioning and ischemic postconditioning, either separately or in combination, after an acute ischemia-reperfusion kidney injury. METHODS: Forty Wistar rats received isoflurane anesthesia and were randomized into 5 groups: 1. the sham group underwent laparotomy; 2. the control group underwent laparotomy and 30 minutes of renal ischemia followed by reperfusion; 3. the preconditioning group underwent laparotomy, ischemic preconditioning, and 30 minutes of renal ischemia followed by reperfusion; 4. the preconditioning and postconditioning group underwent laparotomy, ischemic preconditioning, 30 minutes of renal ischemia, and ischemic postconditioning followed by reperfusion; and 5. the postconditioning group underwent laparotomy, 30 minutes of renal ischemia, and ischemic postconditioning followed by reperfusion. Serum analyses of creatinine and neutrophil gelatinase-associated lipocalin (NGAL) were performed, and renal histology was examined 24 hours later. RESULTS: Severe tubular injury and increases in creatinine were observed in all groups except the sham group. The control group and all ischemic conditioning groups were no different in the degree of renal injury and values of NGAL and creatinine after the injury. CONCLUSIONS: Ischemic preconditioning and ischemic postconditioning, together or separately, are unable to preserve kidney function or exert a protective effect against tubular cell injury after an acute ischemia-reperfusion kidney injury.


Subject(s)
Acute Kidney Injury/prevention & control , Ischemic Postconditioning/methods , Ischemic Preconditioning/methods , Reperfusion Injury/prevention & control , Acute Kidney Injury/pathology , Animals , Male , Rats , Rats, Wistar , Reperfusion Injury/pathology
2.
Mol Hum Reprod ; 24(11): 556-563, 2018 11 01.
Article in English | MEDLINE | ID: mdl-30376129

ABSTRACT

STUDY QUESTION: Can the mediator complex subunit 12 (MED12) mutation and high mobility group AT-hook 2 (HMGA2) overexpression co-occurrence be explained by the alternative mechanism of HMGA2 dysregulation in uterine leiomyomas (UL)? SUMMARY ANSWER: The co-occurrence of MED12 mutation and HMGA2 overexpression, and a negative correlation of five validated or predicted microRNAs that target HMGA2 were reported. WHAT IS KNOWN ALREADY: The recent stratification of UL, according to recurrent and mutually exclusive genomic alterations affecting HMGA2, MED12, fumarate hydratase (FH) and collagen type IV alpha 5-alpha 6 (COL4A5-COL4A6) pointed out the involvement of distinct molecular pathways. However, the mechanisms of regulation involving these drivers are poorly explored. STUDY DESIGN, SIZE, DURATION: A total of 78 UL and 34 adjacent normal myometrium (NM) tissues was collected from 56 patients who underwent hysterectomies at a single institution. The patients were treated at the Department of Gynecology and Obstetrics, School of Medicine, Sao Paulo State University, Botucatu, SP, Brazil, from October 1995 to February 2004. PARTICIPANTS/MATERIALS, SETTING, METHODS: Gene expression profiling was evaluated from fresh frozen tissues and compared with MED12 mutations at exon 2. In addition, RT-qPCR was applied to evaluate the expression levels of HMGA2 and their predictive miRNA regulators: hsa-let-7a, miR-26a, miR-26b, mir-93 and mir-106b. MAIN RESULTS AND THE ROLE OF CHANCE: An unsupervised hierarchical clustering analysis revealed two main clusters with one of them (26 of 42 UL) showing an enrichment of MED12 mutated cases (18 of 26 UL). Increased expression levels of HMGA2 were observed in both clusters, including cases with MED12 mutation (cluster 1:18 UL). A significant HMGA2 overexpression (P < 0.001) in UL in comparison with NM was found. Five miRNAs predicted to regulate HMGA2 were significantly downregulated (P < 0.001) and negatively correlated to HMGA2 expression levels (P < 0.05) in UL. LIMITATIONS REASONS FOR CAUTION: An in vivo functional study was not performed to validate the microRNAs and HMGA2 interaction due to technical limitations. WIDER IMPLICATIONS OF THE FINDINGS: HMGA2 overexpression was detected in a significant number of MED12 mutated ULs, suggesting that these alterations coexist. Furthermore, five miRNAs were described as potential regulators of HMGA2 expression in UL. LARGE-SCALE DATA: Data available in the Gene Expression Omnibus GSE42939. STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (# 2008/58835-2) and Conselho Nacional de Pesquisa (# 485032/2007-4), Brazil. The authors declared having no conflicts of interest.


Subject(s)
HMGA2 Protein/genetics , HMGA2 Protein/metabolism , Leiomyoma/metabolism , MicroRNAs/metabolism , Uterine Neoplasms/metabolism , Adult , Exons/genetics , Female , Gene Expression Profiling , Humans , In Vitro Techniques , Leiomyoma/genetics , MicroRNAs/genetics , Middle Aged , Mutation , Uterine Neoplasms/genetics
3.
J Eur Acad Dermatol Venereol ; 30(8): 1315-20, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27291154

ABSTRACT

BACKGROUND: There is inadequate knowledge on the involvement of oncogenic mechanisms linked to the cyclin (CCND1) gene in lip squamous cell carcinoma (LSCC). OBJECTIVE: The aim of this study was to analyse the implication of cyclin D1 in the malignant transformation of lip lesions. METHODS: We immunohistochemically studied 45 actinic cheilitis cases (15 mild dysplasia, 15 moderate dysplasia, 15 severe dysplasia/carcinoma in situ), 30 LSCC cases with adjacent non-tumour epithelium and 15 normal oral epithelium samples for detection of cyclin D1, ß-catenin and Ki-67. RESULTS: Cyclin D1 and Ki-67 expressions were significantly increased in the basal layer of premalignant epithelia and peripheral layers of tumour nests vs. CONTROLS: Premalignant epithelia had lost their asymmetrical proliferative pattern. CONCLUSION: Lip carcinogenesis was associated with loss of the asymmetrical proliferative pattern, a preventive mechanism against lip oncogenesis, and with cyclin D1 overexpression.


Subject(s)
Cell Proliferation , Cyclin D1/metabolism , Lip Neoplasms/pathology , Lip/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Humans , Lip/metabolism , Lip Neoplasms/metabolism , Male , Middle Aged , Young Adult
4.
Transplant Proc ; 46(5): 1591-3, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24834857

ABSTRACT

BACKGROUND: Melatonin is a free radical scavenger with important actions in the study of renal ischemia and reperfusion (I/R). This study evaluated possible renal protection of high doses of melatonin in an experimental model of I/R in which rats were submitted to acute hyperglycemia under anesthesia with isoflurane. METHOD: Forty-four male Wistar rats, weighing more than 300 g, were randomly divided into 5 groups: G1, sham (n = 10); G2, melatonin (n = 10; 50 mg.kg(-1)); G3, hyperglycemia (n = 9; glucose 2.5 g.kg(-1)); G4, hyperglycemia/melatonin (n = 10; 2.5 g.kg(-1) glucose + melatonin 50 mg.kg(-1)); and G5, I/R (n = 5). In all groups, anesthesia was induced with 4% isoflurane and maintained with 1.5% to 2.0% isoflurane. Intraperitoneal injection of melatonin (G1, G4), glucose (G3, G4), or saline (G1, G5) was performed 40 minutes before left renal ischemia. Serum plasma values for creatinine and glucose were determined at baseline (M1), immediately following reperfusion (M2), and 24 hours after completion of the experiment (M3). Histological analysis was performed to evaluate tubular necrosis (0-5). RESULTS: Serum glucose was higher at M2 in the groups supplemented with glucose, hyperglycemia (356.00 ± 107.83), and hyperglycemia/melatonin (445.3 ± 148.32). Creatinine values were higher at T3 (P = .0001) for I/R (3.6 ± 0.37), hyperglycemia/melatonin (3.9 ± 0.46), and hyperglycemia (3.71 ± 0.69) and lower in the sham (0.79 ± 0.16) and melatonin (2.01 ± 1.01) groups, P < .05. Histology showed no necrosis injury in the G1, lesion grade 2 in the G2, and severe acute tubular necrosis in the G3: (grade 4), G4: (grade 5) and G5: (grade 4) groups (P < .0001). DISCUSSION: Melatonin protected the kidneys submitted to I/R in rats without hyperglycemia; however, this did not occur when the I/R lesion was associated with hyperglycemia. CONCLUSIONS: Due to its antioxidant and antiapoptotic action, melatonin was able to mitigate, but not prevent acute tubular necrosis in rats with hyperglycemia under anesthesia by isoflurane.


Subject(s)
Hyperglycemia/complications , Kidney/drug effects , Melatonin/pharmacology , Reperfusion Injury/prevention & control , Animals , Dose-Response Relationship, Drug , Kidney/blood supply , Kidney/physiopathology , Male , Rats , Rats, Wistar , Reperfusion Injury/complications
5.
Ann Oncol ; 25(1): 69-75, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24285016

ABSTRACT

BACKGROUND: Ataxia telangiectasia-mutated (ATM) gene downexpression has been reported in sporadic breast carcinomas (BC); however, the prognostic value and mechanisms of ATM deregulation remain unclear. PATIENTS AND METHODS: ATM and miRNAs (miR-26a, miR-26b, miR-203, miR-421, miR-664, miR-576-5p and miR-18a) expression levels were evaluated by quantitative real-time PCR (RT-qPCR) in 52 BC and 3 normal breast samples. ATM protein expression was assessed by immunohistochemistry in 968 BC and 35 adjacent normal breast tissues. ATM copy number alteration was detected by array comparative genomic hybridization (aCGH) in 42 tumours. RESULTS: Low ATM levels were associated with tumour grade. Absence of ATM protein expression was associated with distant metastasis (P < 0.001), reduced disease-free survival (DFS, P < 0.001) and cancer-specific survival (CSS, P < 0.001). Multivariate analysis indicated ATM protein expression as an independent prognostic marker for DFS (P = 0.001, HR = 0.579) and CSS (P = 0.001, HR = 0.554). ATM copy number loss was detected in 12% of tumours and associated with lower mRNA levels. miR-421 over-expression was detected in 36.5% of cases which exhibit lower ATM transcript levels (P = 0.075, r = -0.249). CONCLUSIONS: The data suggest that ATM protein expression is an independent prognostic marker in sporadic BC. Gene copy number loss and miR-421 over-expression may be involved in ATM deregulation in BC.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/metabolism , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Ataxia Telangiectasia Mutated Proteins/genetics , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/mortality , Carcinoma, Ductal, Breast/secondary , Case-Control Studies , Disease-Free Survival , Down-Regulation , Female , Gene Dosage , Gene Expression , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasm Grading , Prognosis , Proportional Hazards Models
6.
Braz J Med Biol Res ; 46(3): 207-16, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23558859

ABSTRACT

Human epidermal growth factor receptor 2 (HER2) has been evaluated in breast cancer patients to identify those most likely to benefit from herceptin-targeted therapy. HER2 amplification, detected in 20-30% of invasive breast tumors, is associated with reduced survival and metastasis. The most frequently used technique for evaluating HER2 protein status as a routine procedure is immunohistochemistry (IHC). HER2 copy number alterations have also been evaluated by fluorescence in situ hybridization (FISH) in moderate immunoexpression (IHC 2+) cases. An alternative procedure to evaluate gene amplification is chromogenic in situ hybridization (CISH), which has some advantages over FISH, including the correlation between HER2 status and morphological features. Other methodologies have also been used, such as silver-enhanced in situ hybridization (SISH) and quantitative real-time RT-PCR, to determine the number of HER2 gene copies and expression, respectively. Here we will present a short and comprehensive review of the current advances concerning HER2 evaluation in human breast cancer.


Subject(s)
Breast Neoplasms/genetics , Genes, erbB-2/genetics , In Situ Hybridization, Fluorescence , Biomarkers, Tumor/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chromogenic Compounds , Female , Gene Amplification , Humans , Immunohistochemistry , Real-Time Polymerase Chain Reaction , Sensitivity and Specificity
7.
Braz. j. med. biol. res ; 46(3): 207-216, 15/mar. 2013. tab, graf
Article in English | LILACS | ID: lil-670903

ABSTRACT

Human epidermal growth factor receptor 2 (HER2) has been evaluated in breast cancer patients to identify those most likely to benefit from herceptin-targeted therapy. HER2 amplification, detected in 20-30% of invasive breast tumors, is associated with reduced survival and metastasis. The most frequently used technique for evaluating HER2 protein status as a routine procedure is immunohistochemistry (IHC). HER2 copy number alterations have also been evaluated by fluorescence in situ hybridization (FISH) in moderate immunoexpression (IHC 2+) cases. An alternative procedure to evaluate gene amplification is chromogenic in situ hybridization (CISH), which has some advantages over FISH, including the correlation between HER2 status and morphological features. Other methodologies have also been used, such as silver-enhanced in situ hybridization (SISH) and quantitative real-time RT-PCR, to determine the number of HER2 gene copies and expression, respectively. Here we will present a short and comprehensive review of the current advances concerning HER2 evaluation in human breast cancer.


Subject(s)
Female , Humans , Breast Neoplasms/genetics , /genetics , In Situ Hybridization, Fluorescence , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chromogenic Compounds , Gene Amplification , Immunohistochemistry , Real-Time Polymerase Chain Reaction , Sensitivity and Specificity , Biomarkers, Tumor/genetics
8.
Ann Oncol ; 21(4): 734-740, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19914962

ABSTRACT

BACKGROUND: The clinical relevance of transforming growth factor-beta (TGF-beta)-signalling pathway in breast carcinomas (BCs) remained elusive. This study aimed to evaluate the prognostic value of TGF-beta1 and transforming growth factor-beta type II receptor (TGF-betaRII) expression levels in tumour cells and their association with the established biomarkers in BC. PATIENTS AND METHODS: In 324 BC from patients with long-term follow-up, the TGF-beta1 and TGF-betaRII transcript and protein expression levels were assessed. RESULTS: TGF-beta1 and TGF-betaRII down-expression was significantly associated with BC. Negative TGF-beta1 and TGF-betaRII protein status was associated with the development of distant metastasis (P = 0.003 and P = 0.029, respectively). In multivariate analysis, TGF-beta1-positive tumours were associated with increased disease-free survival (DFS) [hazard ratio (HR) = 0.489, P = 0.003]. TGF-betaRII positivity was an independent prognostic factor for DFS (HR = 0.439, P = 0.001) and overall survival (OS) (HR = 0.409, P = 0.003) in human epidermal growth factor receptor-2 (HER2)-negative patients. Absence of TGF-beta1 and TGF-betaRII proteins in breast tumour cells was significantly associated with metastasis development. CONCLUSIONS: To the best of our knowledge, this is the first report indicating the relevance of HER2 status in discriminating TGF-betaRII as a prognostic marker for DFS and OS in human BC. These data indicate that TGF-betaRII protein analysis in tumour cells could be introduced in clinical practice as additional prognostic biomarker in HER2-negative BC.


Subject(s)
Breast Neoplasms/diagnosis , Carcinoma/diagnosis , Genes, erbB-2 , Protein Serine-Threonine Kinases/genetics , Receptors, Transforming Growth Factor beta/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/mortality , Down-Regulation , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Predictive Value of Tests , Prognosis , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/metabolism , Survival Analysis , Transforming Growth Factor beta1/genetics , Young Adult
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