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1.
Int J Gynecol Cancer ; 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39313300

RESUMO

OBJECTIVE: To evaluate the lymphatic-specific morbidity (specifically, lower extremity lymphedema) associated with laparoscopic management of early-stage endometrial cancer using the sentinel lymph node (SLN) algorithm by type of actual nodal assessment. METHODS: An ambispective study was conducted on consecutive patients surgically treated for apparent early-stage endometrial cancer who underwent laparoscopic staging according to the National Comprehensive Cancer Network SLN algorithm at a single institution from January 2020 to August 2023. Data on patient characteristics, surgical details, and post-operative complications were collected. Lymphedema screening was performed using a validated questionnaire. RESULTS: A total of 239 patients were analyzed, with a questionnaire response rate of 85.4%. The study population was grouped based on actual surgical staging: hysterectomy+SLN (54.8%), hysterectomy+systematic pelvic lymphadenectomy (27.2%), and hysterectomy only (18%). The prevalence of lymphedema was significantly lower in the hysterectomy+SLN group compared with the hysterectomy+systematic pelvic lymphadenectomy group (21.4% vs 44.6%, p=0.003). Multivariable analysis showed a threefold increase in the risk of lymphedema for the hysterectomy+systematic pelvic lymphadenectomy group compared with the hysterectomy+SLN group: OR 3.11 (95% CI 1.47 to 6.58). No significant associations were found between lymphedema and other patient or tumor characteristics. CONCLUSION: In the setting of a laparoscopic approach for early-stage endometrial cancer surgery, SLN mapping is associated with a significant reduction in lymphatic complications compared with a systematic lymph node dissection. Our findings provide additional evidence endorsing the adoption of SLN mapping during minimally invasive surgery for endometrial cancer. This technique ensures comparable diagnostic accuracy and also minimizes complications.

2.
J Minim Invasive Gynecol ; 31(6): 525-532, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38556248

RESUMO

STUDY OBJECTIVE: To investigate postoperative surgical and non-surgical complications that occur within 30 days following myomectomy procedures, whether laparoscopic or via open surgery. DESIGN: Prospective cohort study SETTING: Del Ponte Women's and Children's Hospital, Varese, Italy. PATIENTS: Women undergoing myomectomy either with laparoscopic or open surgery from July 2020 to June 2023 INTERVENTIONS: Data of consecutive patients who underwent abdominal myomectomy procedures, either via laparoscopy or open abdominal surgery were collected. The study examined patient characteristics, size and location of fibroids, surgical data, and complications. Univariate and multivariable analyses were employed to identify factors contributing to postoperative Clavien-Dindo grade ≥ II complications. MEASUREMENTS AND MAIN RESULTS: Overall 383 patients were included in the study. The univariate analysis showed intramural fibroid type (p = .0009), large fibroid size (p = .03), and extended operative times (p = .05) were associated with postoperative complications. Open surgical approach (p <.001) and uterine cavity opening (p = .02) also contributed to complications. Postoperative anemia emerged as the most prevalent complication. In the multivariable analysis, the open surgical approach emerged as the only independent factor associated with an increased risk of grade ≥ II complications (odds ratio 7.37; p <.0001). CONCLUSION: In this study we found an increased likelihood of complications in case of open myomectomy. While the presence of potential selection bias may have impacted this finding, it could provide valuable insights for clinicians and surgical teams in the strategic planning of myomectomy procedures.


Assuntos
Laparoscopia , Leiomioma , Complicações Pós-Operatórias , Miomectomia Uterina , Neoplasias Uterinas , Humanos , Feminino , Miomectomia Uterina/efeitos adversos , Miomectomia Uterina/métodos , Estudos Prospectivos , Adulto , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Leiomioma/cirurgia , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Neoplasias Uterinas/cirurgia , Duração da Cirurgia , Pessoa de Meia-Idade , Resultado do Tratamento , Itália/epidemiologia , Fatores de Risco
3.
J Surg Oncol ; 129(3): 517-522, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37974522

RESUMO

BACKGROUND AND METHODS: Uterine leiomyosarcomas (uLMS) are rare malignant tumors, often incidentally discovered, with an estimated annual incidence of five cases per one million women in the United States. This study aimed to compare the oncological outcomes of two groups of patients: those with uLMS incidentally found during surgery and those who underwent surgery due to suspected or confirmed uLMS before the procedure. The study assessed patients who had undergone hysterectomy and were diagnosed with stage I uLMS at a tertiary gynecologic oncology referral center in Italy between January 2000 and December 2019. Data on patients' baseline characteristics, surgical procedures, and oncological outcomes were collected. The patients were classified into two groups based on whether uLMS was unexpectedly discovered or suspected before the surgery. Survival rates and factors influencing recurrence were analyzed. RESULTS: The study included 36 patients meeting the inclusion criteria, with 12 having preoperatively suspected or proven uLMS and 24 having incidentally discovered uLMS. No significant differences were observed between the two groups regarding disease-free survival (23.7 vs. 27.3 months, log rank = 0.28), disease-specific survival (median not reached, log rank = 0.78), or sites of relapse. Notably, among patients who underwent laparoscopic hysterectomy (compared to open surgery), a significantly higher rate of locoregional recurrence was found (78% vs. 33.3%, p = 0.04). Nevertheless, no significant differences in survival were observed based on the surgical approach. CONCLUSIONS: Preoperative suspicion for uLMS did not seem to impact survival outcomes or the pattern of recurrence. Furthermore, although patients who underwent laparoscopic hysterectomy showed a higher rate of locoregional relapse, this did not affect their overall survival.


Assuntos
Leiomiossarcoma , Neoplasias Pélvicas , Neoplasias Uterinas , Feminino , Humanos , Leiomiossarcoma/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/patologia , Neoplasias Uterinas/cirurgia , Neoplasias Uterinas/patologia , Neoplasias Pélvicas/cirurgia , Histerectomia/métodos , Recidiva
4.
Molecules ; 27(5)2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35268803

RESUMO

Silibinin is the main biologically active component of silymarin extract and consists of a mixture 1:1 of two diastereoisomeric flavonolignans, namely silybin A (1a) and silybin B (1b), which we call here silybins. Despite the high interest in the activity of this flavonolignan, there are still few studies that give due attention to the role of its stereochemistry and, there is still today a strong need to investigate in this area. In this regard, here we report a study concerning the radical scavenger ability and the antiproliferative activity on different cell lines, both of silybins and phosphodiester-linked silybin dimers. An efficient synthetic strategy to obtain silybin dimers in an optical pure form (6aa, 6ab and 6bb) starting from a suitable building block of silybin A and silybin B, obtained by us from natural extract silibinin, was proposed. New dimers show strong antioxidant properties, determined through hydroxyl radical (HO●) scavenging ability, comparable to the value reported for known potent antioxidants such as quercetin. A preliminary screening was performed by treating cells with 10 and 50 µM concentrations for 48 h to identify the most sensitive cell lines. The results show that silibinin compounds were active on Jurkat, A375, WM266, and HeLa, but at the tested concentrations, they did not interfere with the growth of PANC, MCF-7, HDF or U87. In particular, both monomers (1a and 1b) and dimers (6aa, 6ab and 6bb) present selective anti-proliferative activity towards leukemia cells in the mid-micromolar range and are poorly active on normal cells. They exhibit different mechanisms of action in fact all the cells treated with the 1a and 1b go completely into apoptosis, whereas only part of the cells treated with 6aa and 6ab were found to be in apoptosis.


Assuntos
Neoplasias , Silimarina , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Quercetina , Silibina/farmacologia , Silimarina/química , Silimarina/farmacologia
5.
BMC Bioinformatics ; 17(1): 423, 2016 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-27756200

RESUMO

BACKGROUND: Post-transcriptional regulation is a complex mechanism that plays a central role in defining multiple cellular identities starting from a common genome. Modifications in the length of 3'UTRs have been found to play an important role in this context, since alternative 3' UTRs could lead to differences for example in regulation by microRNAs and cellular localization of the transcripts thus altering their fate. RESULTS: We propose a strategy to identify the genes undergoing regulation of 3' UTR length using RNA sequencing data obtained from standard libraries, thus widely applicable to data originally obtained to perform classical differential expression analyses. We decided to exploit previously annotated APA sites from public databases, in contrast with other approaches recently proposed in which the location of the APA site is inferred from the data together with the relative abundance of the isoforms. We demonstrate the reliability of our method by comparing it to the results of other microarray based or specific RNA-seq libraries methods and show that using APA sites databases results in higher sensitivity compared to de novo site prediction approach. CONCLUSIONS: We implemented the algorithm in a Bioconductor package to facilitate its broad usage in the scientific community. The ability of this approach to detect shortening from libraries with a number of reads comparable to that needed for differential expression analyses makes it useful for investigating if alternative polyadenylation is relevant in a certain biological process without requiring specific experimental assays.


Assuntos
Regiões 3' não Traduzidas/genética , Algoritmos , Encéfalo/metabolismo , Neoplasias da Mama/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Poliadenilação/genética , RNA Mensageiro/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Reprodutibilidade dos Testes
6.
Cancer Res ; 76(24): 7231-7241, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27758885

RESUMO

Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3' untranslated region (3' UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3' UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtype-specific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex. Cancer Res; 76(24); 7231-41. ©2016 AACR.


Assuntos
GTP Fosfo-Hidrolases/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Western Blotting , Feminino , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Poliadenilação , Elementos Reguladores de Transcrição/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma , Transfecção , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
7.
Clin Cancer Res ; 22(2): 337-45, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26423797

RESUMO

PURPOSE: In spite of improvements of average benefit from adjuvant/neoadjuvant treatments, there are still individual patients with early breast cancer at high risk of relapse. We explored the association with outcome of robust gene cluster-based metagenes linked to proliferation, ER-related genes, and immune response to identify those high-risk patients. EXPERIMENTAL DESIGN: A total of 3,847 publicly available gene-expression profiles were analyzed (untreated, N = 826; tamoxifen-treated, N = 685; chemotherapy-treated, N = 1,150). Genes poorly performing in formalin-fixed samples were removed. Outcomes of interest were pathologic-complete response (pCR) and distant metastasis-free survival (DMFS). In ER(+)HER2(-), the proliferation and ER-related metagenes were combined to define three risk groups. In HER2(+) and ER(-)HER2(-) risk groups were defined by tertiles of an immune-related metagene. RESULTS: The high-proliferation/low-ER group of ER(+)HER2(-) breast cancer had significantly higher pCR rate [OR, 5.01 (1.76-17.99), P = 0.005], but poorer outcome [HR = 3.73 (1.63-8.51), P = 0.0018] than the low-proliferation/high-ER. A similar association with outcome applied to patients with residual disease (RD) after neoadjuvant chemotherapy (P = 0.01). In ER(-)HER2(-) and HER2(+) breast cancer, immune metagene in the high tertile was linked to higher pCR [33.7% vs. 11.6% in high and low tertile, respectively; OR, 3.87 (1.79-8.95); P = 0.0009]. In ER(-)HER2(-), after adjuvant/neoadjuvant chemotherapy, 5-year DMFS was 85.4% for high-tertile immune metagene, and 43.9% for low tertile. The outcome association was similar in patients with RD (P = 0.0055). In HER2(+) breast cancer treated with chemotherapy the association with risk of relapse was not significant. CONCLUSIONS: We developed metagene-based predictors able to define low and high risk of relapse after adjuvant/neoadjuvant therapy. High-risk patients so defined should be preferably considered for trials with investigational agents.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Metagenoma/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/terapia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Prognóstico , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
8.
Cell Stem Cell ; 15(6): 762-74, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25515522

RESUMO

Mesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer.


Assuntos
Neoplasias da Mama/diagnóstico , Fatores de Transcrição Forkhead/metabolismo , Células-Tronco Mesenquimais/fisiologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/fisiologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Metástase Neoplásica , Prognóstico , Fala/fisiologia , Análise de Sobrevida
9.
Cell Cycle ; 13(11): 1811-26, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24736554

RESUMO

α6ß4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between ß4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different ß4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express ß4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates ß4 expression. We demonstrate that miR-221/222 overexpression results in ß4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving ß4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for ß4 integrin 3'UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven ß4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted "normal" breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates ß4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy.


Assuntos
Neoplasias da Mama/fisiopatologia , Carcinoma Ductal de Mama/fisiopatologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Integrina beta4/metabolismo , MicroRNAs/metabolismo , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAM17 , Análise de Variância , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Primers do DNA/genética , Progressão da Doença , Feminino , Inativação Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Luciferases , Invasividade Neoplásica/genética , RNA Interferente Pequeno/genética , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/metabolismo
10.
Methods Mol Biol ; 1125: 141-4, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24590786

RESUMO

Gene regulation at the posttranscriptional level is often mediated by trans-acting factors binding the 3' untranslated region (3' UTR) of messenger RNAs (mRNAs). Alternative mRNA isoforms differing only in their 3' UTR can thus be differentially regulated, and it has been recently shown that this mechanism is indeed used by the cell to alter gene regulation effected by microRNAs and RNA-binding proteins, especially in highly proliferating contexts. Here we describe a computational method to analyze alternative 3' UTR isoforms in gene expression profiling datasets obtained with Affymetrix 3' IVT microarrays. The approach we describe allows the analysis of 3' UTR isoform usage in thousands of publicly available gene expression datasets, including many retrospective studies of cancer patients equipped with clinical data.


Assuntos
Regiões 3' não Traduzidas/genética , MicroRNAs/genética , Poliadenilação/fisiologia , Humanos , Poliadenilação/genética , Isoformas de RNA/genética
11.
PLoS One ; 9(1): e86511, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24489733

RESUMO

Formalin fixed paraffin-embedded (FFPE) tumor specimens are the conventionally archived material in clinical practice, representing an invaluable tissue source for biomarkers development, validation and routine implementation. For many prospective clinical trials, this material has been collected allowing for a prospective-retrospective study design which represents a successful strategy to define clinical utility for candidate markers. Gene expression data can be obtained even from FFPE specimens with the broadly used Affymetrix HG-U133 Plus 2.0 microarray platform. Nevertheless, important major discrepancies remain in expression data obtained from FFPE compared to fresh-frozen samples, prompting the need for appropriate data processing which could help to obtain more consistent results in downstream analyses. In a publicly available dataset of matched frozen and FFPE expression data, the performances of different normalization methods and specifically designed Chip Description Files (CDFs) were compared. The use of an alternative CDFs together with fRMA normalization significantly improved frozen-FFPE sample correlations, frozen-FFPE probeset correlations and agreement of differential analysis between different tumor subtypes. The relevance of our optimized data processing was assessed and validated using two independent datasets. In this study we demonstrated that an appropriate data processing can significantly improve the reliability of gene expression data derived from FFPE tissues using the standard Affymetrix platform. Tools for the implementation of our data processing algorithm are made publicly available at http://www.biocut.unito.it/cdf-ffpe/.


Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica/estatística & dados numéricos , Expressão Gênica , Linfoma de Células B/genética , Análise Serial de Tecidos/estatística & dados numéricos , Algoritmos , Neoplasias da Mama/patologia , Bases de Dados Factuais , Feminino , Formaldeído , Perfilação da Expressão Gênica/instrumentação , Perfilação da Expressão Gênica/métodos , Humanos , Linfoma de Células B/patologia , Inclusão em Parafina , Fixação de Tecidos
12.
Cell Cycle ; 12(15): 2409-22, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23839042

RESUMO

Understanding transcriptional changes during cancer progression is of crucial importance to develop new and more efficacious diagnostic and therapeutic approaches. It is well known that ErbB2 is overexpressed in about 25% of human invasive breast cancers. We have previously demonstrated that p130Cas overexpression synergizes with ErbB2 in mammary cell transformation and promotes ErbB2-dependent invasion in three-dimensional (3D) cultures of human mammary epithelial cells. Here, by comparing coding and non-coding gene expression profiles, we define the invasive signatures associated with concomitant p130Cas overexpression and ErbB2 activation in 3D cultures of mammary epithelial cells. Specifically, we have found that genes involved in amino acids synthesis (CBS, PHGDH), cell motility, migration (ITPKA, PRDM1), and angiogenesis (HEY1) are upregulated, while genes involved in inflammatory response (SAA1, S100A7) are downregulated. In parallel, we have shown that the expression of specific miRNAs is altered. Among these, miR-200b, miR-222, miR-221, miR-R210, and miR-424 are upregulated, while miR-27a, miR-27b, and miR-23b are downregulated. Overall, this study presents, for the first time, the gene expression changes underlying the invasive behavior following p130Cas overexpression in an ErbB2 transformed mammary cell model.


Assuntos
Proteína Substrato Associada a Crk/metabolismo , Células Epiteliais/metabolismo , Glândulas Mamárias Humanas/patologia , Receptor ErbB-2/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Transformada , Movimento Celular , Células Epiteliais/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metionina Sulfóxido Redutases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas dos Microfilamentos , Invasividade Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Fosfoglicerato Desidrogenase/metabolismo , Proteína A7 Ligante de Cálcio S100 , Proteínas S100/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma , Regulação para Cima
13.
Biochem Biophys Res Commun ; 438(1): 90-6, 2013 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-23872064

RESUMO

miR-21 is overexpressed in tumors and it displays oncogenic activity. Here, we show that expression of miR-21 in primary tumors anticorrelates with KRIT1/CCM1, an interacting partner of the Ras-like GTPase Rap1, involved in Cerebral Cavernous Malformations (CCM). We present evidences that miR-21 silences KRIT1 by targeting its mRNA 3'UTR and that this interaction is involved in tumor growth control. In fact, miR-21 over-expression or KRIT1 knock-down promote anchorage independent tumor cell growth compared to controls, whereas the opposite is observed when anti-miR-21 or KRIT1 overexpression are employed. Our findings suggest that miR-21 promotes tumor cell growth, at least in part, by down-modulating the potential tumor suppressor KRIT1.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Proteína KRIT1 , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas/genética
14.
Nucl Med Commun ; 34(7): 638-44, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23719113

RESUMO

OBJECTIVE: The objective of the study was to underline the importance of three-phase bone scintigraphy at the time of diagnosis in children with suspected osteoid osteoma (OO) who are eligible for radiofrequency ablation. METHODS: Fifty-three patients (13 girls; mean age 7.2 years, 20% younger than 10 years of age) who underwent bone scintigraphy for suspected OO between 2005 and 2010 were included in the study, of whom 46 underwent a radiography at diagnosis. Computed tomography-guided biopsy was performed in all patients after bone scintigraphy, and radiofrequency ablation was performed following biopsy in patients with OO; ablation efficacy was confirmed by MRI at 1, 3, 12 and 18 months. RESULTS: The radiographic results were negative in 27/46 patients and was unclear in 19. Bone scintigraphy showed lesions in 53/53 patients, of whom 51 patients had a typical pattern of osteoma and nine patients required an additional scan with a pinhole collimator. Histological examination showed OO in 51/53 patients (3/51 intramedullary), Ewing's sarcoma in 1/53 patients, and chronic osteomyelitis in 1/53 patients. CONCLUSION: Any child with recurrent nocturnal pain and/or limb swelling should undergo radiography of the involved skeletal segment, which is the first-choice diagnostic method in the clinical suspicion of OO. In the event of ambiguous or negative radiographic results, bone scintigraphy is needed to exclude other pathologic conditions and to confirm the diagnosis. In children with recurrent but not well-localized bone pain in which OO is strongly suspected for signs and symptoms, a bone scan can help detect the lesion. The diagnostic accuracy of the bone scan, particularly for the appendicular skeleton, can be improved by pinhole collimator acquisition.


Assuntos
Técnicas de Ablação , Osso e Ossos/diagnóstico por imagem , Osteoma Osteoide/diagnóstico por imagem , Osteoma Osteoide/cirurgia , Terapia por Radiofrequência , Osso e Ossos/cirurgia , Criança , Feminino , Seguimentos , Humanos , Masculino , Osteoma Osteoide/patologia , Cintilografia , Estudos Retrospectivos
15.
PLoS One ; 7(2): e31129, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22347440

RESUMO

A major part of the post-transcriptional regulation of gene expression is affected by trans-acting elements, such as microRNAs, binding the 3' untraslated region (UTR) of their target mRNAs. Proliferating cells partly escape this type of negative regulation by expressing shorter 3' UTRs, depleted of microRNA binding sites, compared to non-proliferating cells. Using large-scale gene expression datasets, we show that a similar phenomenon takes place in breast and lung cancer: tumors expressing shorter 3' UTRs tend to be more aggressive and to result in shorter patient survival. Moreover, we show that a gene expression signature based only on the expression ratio of alternative 3' UTRs is a strong predictor of survival in both tumors. Genes undergoing 3'UTR shortening in aggressive tumors of the two tissues significantly overlap, and several of them are known to be involved in tumor progression. However the pattern of 3' UTR shortening in aggressive tumors in vivo is clearly distinct from analogous patterns involved in proliferation and transformation.


Assuntos
Regiões 3' não Traduzidas , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , MicroRNAs/genética , Prognóstico , Interferência de RNA
16.
EMBO J ; 30(10): 1990-2007, 2011 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-21468029

RESUMO

Malignant melanoma is fatal in its metastatic stage. It is therefore essential to unravel the molecular mechanisms that govern disease progression to metastasis. MicroRNAs (miRs) are endogenous non-coding RNAs involved in tumourigenesis. Using a melanoma progression model, we identified a novel pathway controlled by miR-214 that coordinates metastatic capability. Pathway components include TFAP2C, homologue of a well-established melanoma tumour suppressor, the adhesion receptor ITGA3 and multiple surface molecules. Modulation of miR-214 influences in vitro tumour cell movement and survival to anoikis as well as extravasation from blood vessels and lung metastasis formation in vivo. Considering that miR-214 is known to be highly expressed in human melanomas, our data suggest a critical role for this miRNA in disease progression and the establishment of distant metastases.


Assuntos
Regulação da Expressão Gênica , Melanoma/patologia , Melanoma/secundário , MicroRNAs/metabolismo , Metástase Neoplásica/patologia , Fator de Transcrição AP-2/biossíntese , Animais , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Humanos , Integrinas/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , MicroRNAs/genética
17.
PLoS One ; 6(2): e14737, 2011 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-21386884

RESUMO

INTRODUCTION: The classification of breast cancer patients into risk groups provides a powerful tool for the identification of patients who will benefit from aggressive systemic therapy. The analysis of microarray data has generated several gene expression signatures that improve diagnosis and allow risk assessment. There is also evidence that cell proliferation-related genes have a high predictive power within these signatures. METHODS: We thus constructed a gene expression signature (the DM signature) using the human orthologues of 108 Drosophila melanogaster genes required for either the maintenance of chromosome integrity (36 genes) or mitotic division (72 genes). RESULTS: The DM signature has minimal overlap with the extant signatures and is highly predictive of survival in 5 large breast cancer datasets. In addition, we show that the DM signature outperforms many widely used breast cancer signatures in predictive power, and performs comparably to other proliferation-based signatures. For most genes of the DM signature, an increased expression is negatively correlated with patient survival. The genes that provide the highest contribution to the predictive power of the DM signature are those involved in cytokinesis. CONCLUSION: This finding highlights cytokinesis as an important marker in breast cancer prognosis and as a possible target for antimitotic therapies.


Assuntos
Neoplasias da Mama/mortalidade , Carcinoma/mortalidade , Drosophila melanogaster/genética , Perfilação da Expressão Gênica , Mitose/genética , Adulto , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/fisiologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Carcinoma/diagnóstico , Carcinoma/genética , Biologia Computacional , Feminino , Genes de Insetos , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Homologia de Sequência , Análise de Sobrevida
18.
Skeletal Radiol ; 40(12): 1523-30, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21404054

RESUMO

OBJECTIVE: To report on the particular imaging features and high success rate of cold mode radio-frequency thermal ablation (RFTA) as the treatment of choice for intramedullary osteoid osteoma. MATERIALS AND METHODS: The study population consisted of 51 patients (39 males, 12 females; mean age 7.2 years; 11 patients under 6 years of age, including 7 males and 4 females) who underwent RFTA for osteoid osteoma and were retrospectively observed. The affected sites were the tibia (n = 22, 43%), femur (n = 13, 25%), pelvis (n = 5, 10%), anklebone (n = 3, 6%), humerus (n = 2, 4%), sacrum (n = 2, 4%), heel, radium, patella ,and rib (n = 1, 2%), respectively. Three patients had tibial intramedullary osteoid osteoma (14% of the tibial lesions, 6% of all cases). Cold mode RFTA was performed for these three patients to obtain a large ablation area without positioning two probes. The noncooled mode was used to treat cortical and subperiosteal lesions. RESULTS: Following RFTA, all patients were pain-free and in good clinical condition. In the intramedullary osteoid osteoma group, no recurrences were observed during the 24-month follow-up period, but one patient, who was affected by cortical osteoid osteoma, required two RFTA treatments to heal completely. CONCLUSION: Children less than 6 years of age with recurrent nocturnal pain and limb swelling should be investigated for intramedullary osteoid osteoma. Once confirmed, CT-guided RFTA should be the first treatment for intramedullary osteoid osteomas because of the high success rate and reduced invasivity, especially with cold mode RFTA. The outcome is related to the disappearance of pain, and the efficacy may be checked shortly after treatment with MR imaging to evaluate the absence of lesion in the ablation area.


Assuntos
Neoplasias Ósseas/terapia , Osteoma Osteoide/terapia , Adolescente , Neoplasias Ósseas/diagnóstico , Ablação por Cateter , Criança , Pré-Escolar , Feminino , Tomografia Computadorizada Quadridimensional , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Osteoma Osteoide/diagnóstico , Estudos Retrospectivos , Adulto Jovem
19.
Arch Ital Urol Androl ; 75(1): 1-5, 2003 Mar.
Artigo em Italiano | MEDLINE | ID: mdl-12741336

RESUMO

The choice of urinary diversion is conditioned to patient's disease, performance status, age and life style. Ureterointestinal anastomosis is a critical stage in urinary diversion, allowing urinary transit and preventing reflux. We have examined urinary diversion frequently used in our clinical practice. In ureterosigmoidostomy and MAINZ pouch II , ureterointestinal anastomosis isn't refluent. Ileal conduit, reserved to patient with advanced disease and/or low life expectation, normally the implantation is direct. In continent reservoir and orthotopic neobladder, detubularization produces low pressure. In these urinary diversion anti-reflux anastomosis isn't mandatory, because the risk of stenosis is higher. Urinary infection is an important criterion in choice of anastomosis. After all is emphasized that success of ureterointestinal implantation doesn't depend on surgeon's level of experience.


Assuntos
Derivação Urinária , Colo/cirurgia , Colo Sigmoide/cirurgia , Constrição Patológica/etiologia , Dilatação Patológica/etiologia , Humanos , Complicações Pós-Operatórias , Reoperação , Ureterostomia , Derivação Urinária/efeitos adversos , Derivação Urinária/métodos , Infecções Urinárias/etiologia
20.
Arch Ital Urol Androl ; 74(2): 90-4, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12161944

RESUMO

OBJECTIVE: The noninvasive method for estimating bladder weight (UEBW, Ultrasound Estimated Bladder Weight) can be used as a measure of bladder hypertrophy and may have clinical use for evaluating intravesical obstruction in male patients. The aim of this study was to assess whether, in patients with bladder outlet obstruction (BOO), tamsulosin treatment produced any significant change in UEBW. METHODS: 32 male patients with lower urinary tract symptoms (LUTS) suggestive of BOO [benign prostatic hyperflesia (BPH) was the apparent cause of BOO] were enrolled in an open pilot study. At baseline, physical examination, ECG, hematochemical tests, urine analysis, urine culture, urodynamics, urethrocystography, transrectal ultrasound, UEBW and symptom score were performed. Using the International Continence Society (ICS) nomogram, patients were assigned to three different groups: obstructed, not obstructed and equivocal. Only patients in the obstructed and equivocal categories were treated with tamsulosin 0.4 mg once daily for 6 months. Follow-up for all patients took place after 30 days, 3 and 6 months of treatment. RESULTS: In the obstructed group of patients, the decrease in UEBW was observed at 30 days and maintained up to 6 months, with a significantly improved Qmax. A statistically significant correlation was found between UEBW and postvoid residual urine (PVR) and Abrams-Griffith number (AG). CONCLUSIONS: The results of this study suggest a significant change in UEBW during tamsulosin treatment. The change observed might be suggestive of a therapeutic effect of tamsulosin on the detrusor muscle. Further and more extensive studies are needed in order to confirm a possible therapeutic effect of tamsulosin on the detrusor muscle.


Assuntos
Antagonistas Adrenérgicos alfa/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Sulfonamidas/uso terapêutico , Bexiga Urinária/patologia , Antagonistas Adrenérgicos alfa/farmacologia , Idoso , Antropometria/métodos , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/diagnóstico por imagem , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Tamanho do Órgão , Projetos Piloto , Hiperplasia Prostática/complicações , Hiperplasia Prostática/diagnóstico por imagem , Sulfonamidas/farmacologia , Tansulosina , Ultrassonografia , Bexiga Urinária/diagnóstico por imagem , Obstrução do Colo da Bexiga Urinária/diagnóstico por imagem , Obstrução do Colo da Bexiga Urinária/etiologia
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