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[PMID]:28453704
[Au] Autor:Lesurf R; Griffith OL; Griffith M; Hundal J; Trani L; Watson MA; Aft R; Ellis MJ; Ota D; Suman VJ; Meric-Bernstam F; Leitch AM; Boughey JC; Unzeitig G; Buzdar AU; Hunt KK; Mardis ER
[Ad] Endereço:McDonnell Genome Institute at Washington University School of Medicine, St Louis, USA
[Ti] Título:Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial.
[So] Source:Ann Oncol;28(5):1070-1077, 2017 05 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. Patients and methods: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. Results: We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. Conclusion: The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. ClinicalTrials.gov identifiers: NCT00513292, NCT00353483.
[Mh] Termos MeSH primário: Antineoplásicos Imunológicos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Trastuzumab/uso terapêutico
[Mh] Termos MeSH secundário: Idoso
Neoplasias da Mama/genética
Quimioterapia Adjuvante
Variações do Número de Cópias de DNA
Feminino
Estudos de Associação Genética
Genoma Humano
Mutação em Linhagem Germinativa
Seres Humanos
Mutação INDEL
Meia-Idade
Terapia Neoadjuvante
Polimorfismo de Nucleotídeo Único
Receptor ErbB-2/metabolismo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Immunological); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx048


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[PMID]:27773809
[Au] Autor:Jung B; Staudacher JJ; Beauchamp D
[Ad] Endereço:University of Illinois at Chicago, Chicago, Illinois. Electronic address: bjung@uic.edu.
[Ti] Título:Transforming Growth Factor ß Superfamily Signaling in Development of Colorectal Cancer.
[So] Source:Gastroenterology;152(1):36-52, 2017 Jan.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transforming growth factor (TGF)-ß cytokines signal via a complex network of pathways to regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. A high percentage of colorectal tumors contain mutations that disrupt TGF-ß family member signaling. We review how TGF-ß family member signaling is altered during development of colorectal cancer, models of study, interaction of pathways, and potential therapeutic strategies.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
Neoplasias Colorretais/metabolismo
Receptores de Fatores de Crescimento Transformadores beta/genética
Transdução de Sinais
Proteínas Smad/genética
Fator de Crescimento Transformador beta/genética
Fator de Crescimento Transformador beta/metabolismo
[Mh] Termos MeSH secundário: Ativinas/metabolismo
Animais
Proteínas Morfogenéticas Ósseas/metabolismo
Neoplasias Colorretais/imunologia
Mutação em Linhagem Germinativa
Homeostase
Seres Humanos
Camundongos
Camundongos Knockout
Receptores de Fatores de Crescimento Transformadores beta/imunologia
Proteínas Smad/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Bone Morphogenetic Proteins); 0 (Receptors, Transforming Growth Factor beta); 0 (Smad Proteins); 0 (Transforming Growth Factor beta); 104625-48-1 (Activins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:28460635
[Au] Autor:Chen I; Mathews-Greiner L; Li D; Abisoye-Ogunniyan A; Ray S; Bian Y; Shukla V; Zhang X; Guha R; Thomas C; Gryder B; Zacharia A; Beane JD; Ravichandran S; Ferrer M; Rudloff U
[Ad] Endereço:Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA.
[Ti] Título:Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer.
[So] Source:J Transl Med;15(1):92, 2017 May 01.
[Is] ISSN:1479-5876
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Patients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease. METHODS: In order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells. RESULTS: Unsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1-ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function. CONCLUSION: Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.
[Mh] Termos MeSH primário: Caderinas/deficiência
Avaliação Pré-Clínica de Medicamentos
Perfilação da Expressão Gênica
Ensaios de Triagem em Larga Escala
Neoplasias Gástricas/tratamento farmacológico
Neoplasias Gástricas/genética
[Mh] Termos MeSH secundário: Adulto
Caderinas/genética
Linhagem Celular Tumoral
Diglicerídeos/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica
Predisposição Genética para Doença
Mutação em Linhagem Germinativa/genética
Seres Humanos
Fosfatos de Inositol/metabolismo
Masculino
Linhagem
Reprodutibilidade dos Testes
Neoplasias Gástricas/patologia
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CDH1 protein, human); 0 (Cadherins); 0 (Diglycerides); 0 (Inositol Phosphates); 0 (inositol 3,4,5-trisphosphate); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1186/s12967-017-1197-5


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[PMID]:27776349
[Au] Autor:De Summa S; Guida M; Tommasi S; Strippoli S; Pellegrini C; Fargnoli MC; Pilato B; Natalicchio I; Guida G; Pinto R
[Ad] Endereço:IRCCS Istituto Tumori "Giovanni Paolo II", Molecular Genetics Laboratory, Bari, Italy.
[Ti] Título:Genetic profiling of a rare condition: co-occurrence of albinism and multiple primary melanoma in a Caucasian family.
[So] Source:Oncotarget;8(18):29751-29759, 2017 May 02.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology.To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes.In this study, we evaluated genes involved in melanoma predisposition (CDKN2A, CDK4, MC1R, MITF, POT1, RB1, MGMT, BRCA1, BRCA2), pathogenesis (BRAF, NRAS, PIK3CA, KIT, PTEN), skin/hair pigmentation (MC1R, MITF) and in immune pathways (CTLA4) to individuate alterations able to explain the rare onset of MPM and OCA in indexes and the transmission in their pedigree.From the analysis of the pedigree, we were able to identify a "protective" haplotype with respect to MPM, including MGMT p.I174V alteration. The second generation offspring is under strict follow up as some of them have a higher risk of developing MPM according to our model.
[Mh] Termos MeSH primário: Albinismo/genética
Estudos de Associação Genética
Predisposição Genética para Doença
Mutação em Linhagem Germinativa
Melanoma/genética
Mutação
Neoplasias Primárias Múltiplas/genética
[Mh] Termos MeSH secundário: Albinismo/diagnóstico
Biomarcadores
Biologia Computacional/métodos
Metilação de DNA
Metilases de Modificação do DNA/química
Metilases de Modificação do DNA/genética
Análise Mutacional de DNA
Enzimas Reparadoras do DNA/química
Enzimas Reparadoras do DNA/genética
Família
Feminino
Genótipo
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Melanoma/diagnóstico
Meia-Idade
Modelos Moleculares
Anotação de Sequência Molecular
Neoplasias Primárias Múltiplas/diagnóstico
Linhagem
Filogenia
Conformação Proteica
Irmãos
Proteínas Supressoras de Tumor/química
Proteínas Supressoras de Tumor/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Tumor Suppressor Proteins); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.63 (MGMT protein, human); EC 6.5.1.- (DNA Repair Enzymes)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.12777


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[PMID]:27776352
[Au] Autor:Toomey S; Madden SF; Furney SJ; Fan Y; McCormack M; Stapleton C; Cremona M; Cavalleri GL; Milewska M; Elster N; Carr A; Fay J; Kay EW; Kennedy S; Crown J; Gallagher WM; Hennessy BT; Eustace AJ
[Ad] Endereço:Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Ireland.
[Ti] Título:The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer.
[So] Source:Oncotarget;7(46):75518-75525, 2016 Nov 15.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Trastuzumab treatment for women with HER2-positive breast cancer (BC) resulted in the significant improvement of both relapse free survival (RFS) and overall survival (OS). However, many women who are classified as HER2-positive do not respond. Many studies have focused on the role of somatic mutations rather than germline polymorphisms in trastuzumab resistance. RESULTS: We completed an Agena MassArray screen of 10 ERBB-family single nucleotide polymorphisms (SNPs) in 194 adjuvant trastuzumab treated HER2-positive BC patients. SNPs in EGFR genes have a significant association with RFS and OS. Patients with the minor allele of EGFR N158N had significantly worse OS (hazard ratio (HR) = 4.01, (confidence interval (CI) = 1.53- 10.69), p = 0.05) relative to those with either the heterozygous or wild-type (WT) allele. Patients with the minor allele of EGFR T903T (HR = 3.52, (CI = 1.38- 8.97), p = 0.05) had worse RFS relative to those with either the heterozygous or WT allele. PATIENTS AND METHODS: Using next generation sequencing (NGS) we identified ERBB-family (EGFR, HER2, HER3 and HER4) single nucleotide polymorphisms (SNPs) that occurred in 2 or more patients of a 32 HER2-positive BC patient cohort. Agena MassArray analysis confirmed the frequency of these SNPs in 194 women with HER2-positive BC who received trastuzumab in the adjuvant setting. Using Kaplan-Meier estimates and Cox regression analysis we correlated the presence of ERBB-family SNPs with both RFS and OS. CONCLUSIONS: The presence of germline ERBB-family SNPs may play an important role in how a patient responds to adjuvant trastuzumab, and clinical assessment of these SNPs by targeted genetic screening of patients' blood may be important to stratify patients for treatment.
[Mh] Termos MeSH primário: Neoplasias da Mama/genética
Neoplasias da Mama/mortalidade
Mutação em Linhagem Germinativa
Polimorfismo de Nucleotídeo Único
Receptor ErbB-2/genética
[Mh] Termos MeSH secundário: Alelos
Antineoplásicos Imunológicos/uso terapêutico
Biomarcadores Tumorais
Neoplasias da Mama/tratamento farmacológico
Quimioterapia Adjuvante
Feminino
Genótipo
Seres Humanos
Prognóstico
Modelos de Riscos Proporcionais
Trastuzumab/uso terapêutico
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Immunological); 0 (Biomarkers, Tumor); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.12782


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[PMID]:28465371
[Au] Autor:Castellucci E; He T; Goldstein DY; Halmos B; Chuy J
[Ad] Endereço:Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
[Ti] Título:DNA Polymerase É› Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity.
[So] Source:Oncologist;22(5):497-502, 2017 May.
[Is] ISSN:1549-490X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Deficiencies in DNA repair due to mutations in the exonuclease domain of DNA polymerase É› have recently been described in a subset of cancers characterized by an ultramutated and microsatellite stable (MSS) phenotype. This alteration in DNA repair is distinct from the better-known mismatch repair deficiencies which lead to microsatellite instability (MSI) and an increased tumor mutation burden. Instead, mutations in lead to impaired proofreading intrinsic to Pol É› during DNA replication resulting in a dramatically increased mutation rate. Somatic mutations of Pol É› have been found most frequently in endometrial and colorectal cancers (CRC) and can lead to a unique familial syndrome in the case of germline mutations. While other key genomic abnormalities, such as MSI, have known prognostic and treatment implications, in this case it is less clear. As molecular genotyping of tumors becomes routine in the care of cancer patients, less common, but potentially actionable findings such as these mutations could be overlooked unless appropriate algorithms are in place. We present two cases of metastatic CRC with a mutation, both of which are ultramutated and MSS. The basic biochemical mechanisms leading to a unique phenotype in deficiency as well as challenges faced with interpreting the genomic profiling of tumors in this important subset of patients and the potential clinical implications will be discussed here. 2017;22:497-502 KEY POINTS: Clinicians should recognize that tumors with high tumor mutation burden and that are microsatellite stable may harbor a mutation, which is associated with an ultramutated phenotype.Work-up for deficiency should indeed become part of the routine molecular testing paradigm for patients with colorectal cancer.This subset of patients may benefit from clinical trials where the higher number of mutation-associated neoantigens and defect in DNA repair may be exploited therapeutically.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
DNA Polimerase II/genética
Instabilidade de Microssatélites
Proteínas de Ligação a Poli-ADP-Ribose/genética
Prognóstico
[Mh] Termos MeSH secundário: Neoplasias Colorretais/patologia
DNA Polimerase II/deficiência
Reparo do DNA/genética
Genótipo
Mutação em Linhagem Germinativa/genética
Seres Humanos
Masculino
Meia-Idade
Metástase Neoplásica
Fenótipo
Proteínas de Ligação a Poli-ADP-Ribose/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Poly-ADP-Ribose Binding Proteins); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.7 (POLE protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1634/theoncologist.2017-0034


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[PMID]:29384852
[Au] Autor:Jordan JT; Smith MJ; Walker JA; Erdin S; Talkowski ME; Merker VL; Ramesh V; Cai W; Harris GJ; Bredella MA; Seijo M; Suuberg A; Gusella JF; Plotkin SR
[Ad] Endereço:Department of Neurology.
[Ti] Título:Pain correlates with germline mutation in schwannomatosis.
[So] Source:Medicine (Baltimore);97(5):e9717, 2018 Feb.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Schwannomatosis has been linked to germline mutations in the SMARCB1 and LZTR1 genes, and is frequently associated with pain.In a cohort study, we assessed the mutation status of 37 patients with clinically diagnosed schwannomatosis and compared to clinical data, whole body MRI (WBMRI), visual analog pain scale, and Short Form 36 (SF-36) bodily pain subscale.We identified a germline mutation in LZTR1 in 5 patients (13.5%) and SMARCB1 in 15 patients (40.5%), but found no germline mutation in 17 patients (45.9%). Peripheral schwannomas were detected in 3 LZTR1-mutant (60%) and 10 SMARCB1-mutant subjects (66.7%). Among those with peripheral tumors, the median tumor number was 4 in the LZTR1 group (median total body tumor volume 30 cc) and 10 in the SMARCB1 group (median volume 85cc), (P=.2915 for tumor number and P = .2289 for volume). mutation was associated with an increased prevalence of spinal schwannomas (100% vs 41%, P = .0197). The median pain score was 3.9/10 in the LZTR1 group and 0.5/10 in the SMARCB1 group (P = .0414), and SF-36 pain-associated quality of life was significantly worse in the LZTR1 group (P = .0106). Pain scores correlated with total body tumor volume (rho = 0.32471, P = .0499), but not with number of tumors (rho = 0.23065, P = .1696).We found no significant difference in quantitative tumor burden between mutational groups, but spinal schwannomas were more common in LZTR1-mutant patients. Pain was significantly higher in LZTR1-mutant than in SMARCB1-mutant patients, though spinal tumor location did not significantly correlate with pain. This suggests a possible genetic association with schwannomatosis-associated pain.
[Mh] Termos MeSH primário: Dor do Câncer/genética
Mutação em Linhagem Germinativa
Neurilemoma/genética
Neurofibromatoses/genética
Neoplasias Cutâneas/genética
[Mh] Termos MeSH secundário: Adulto
Dor do Câncer/diagnóstico por imagem
Dor do Câncer/fisiopatologia
Estudos de Coortes
Feminino
Estudos de Associação Genética
Seres Humanos
Imagem por Ressonância Magnética
Masculino
Meia-Idade
Neurilemoma/diagnóstico por imagem
Neurilemoma/fisiopatologia
Neurofibromatoses/diagnóstico por imagem
Neurofibromatoses/fisiopatologia
Medição da Dor
Qualidade de Vida
Proteína SMARCB1/genética
Neoplasias Cutâneas/diagnóstico por imagem
Neoplasias Cutâneas/fisiopatologia
Fatores de Transcrição/genética
Carga Tumoral
Imagem Corporal Total
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (LZTR1 protein, human); 0 (SMARCB1 Protein); 0 (SMARCB1 protein, human); 0 (Transcription Factors)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009717


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[PMID]:29248130
[Au] Autor:Capoluongo E; Ellison G; López-Guerrero JA; Penault-Llorca F; Ligtenberg MJL; Banerjee S; Singer C; Friedman E; Markiefka B; Schirmacher P; Büttner R; van Asperen CJ; Ray-Coquard I; Endris V; Kamel-Reid S; Percival N; Bryce J; Röthlisberger B; Soong R; de Castro DG
[Ad] Endereço:Catholic University of the Sacred Heart and A. Gemelli Teaching Hospital Foundation, Rome, Italy.
[Ti] Título:Guidance Statement On BRCA1/2 Tumor Testing in Ovarian Cancer Patients.
[So] Source:Semin Oncol;44(3):187-197, 2017 06.
[Is] ISSN:1532-8708
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3%-9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin-fixed, paraffin-embedded specimens. The current manuscript reviews some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements.
[Mh] Termos MeSH primário: Proteína BRCA1/genética
Proteína BRCA2/genética
Testes Genéticos
Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico
Neoplasias Ovarianas/genética
[Mh] Termos MeSH secundário: Feminino
Mutação em Linhagem Germinativa
Síndrome Hereditária de Câncer de Mama e Ovário/genética
Seres Humanos
Neoplasias Ovarianas/tratamento farmacológico
Ftalazinas/uso terapêutico
Piperazinas/uso terapêutico
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
Guias de Prática Clínica como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (Phthalazines); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:29309627
[Au] Autor:Kharade SS; Parekh VI; Agarwal SK
[Ad] Endereço:Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
[Ti] Título:Functional Defects From Endocrine Disease-Associated Mutations in HLXB9 and Its Interacting Partner, NONO.
[So] Source:Endocrinology;159(2):1199-1212, 2018 02 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The insulin-secreting pancreatic neuroendocrine tumors, insulinomas, characterized by increased pancreatic islet ß-cell proliferation, express the phosphorylated isoform of the ß-cell differentiation factor HLXB9 that interacts with NONO/p54NRB, a survival factor. Interestingly, two different homozygous germline mutations in HLXB9, p.F248L and p.F272L, were reported in neonatal diabetes, a condition with functional ß-cell deficiency. Also, two somatic heterozygous NONO mutations were found in endocrine-related tumors, p.H146R (parathyroid) and p.R293H (small intestine neuroendocrine tumor). However, the biological consequence of the mutations, and the role of HLXB9-NONO interaction in normal or abnormal ß cells, is not known. Expression, localization, and functional analysis of the clinically relevant HLXB9 and NONO mutants showed that HLXB9/p.F248L mutant localized in the nucleus but lacked phosphorylation, and NONO/p.R293H mutant was structurally impaired. The HLXB9 and NONO mutants retained the ability to interact, and overexpression of wild-type or mutant HXLB9 in MIN6 cells suppressed cell proliferation. To further understand the biological consequence of the HLXB9-NONO interaction, we mapped the NONO-interacting region in HLXB9. An 80-amino acid conserved region of HLXB9 could compete with full-length HLXB9 to interact with NONO; however, in functional assays, nuclear expression of this HLXB9-conserved region in MIN6 cells did not interfere with cell proliferation. Overall, our results highlight the importance of HLXB9 in conditions of ß-cell excess (insulinomas) and in conditions of ß-cell loss or dysfunction (diabetes). Our studies implicate therapeutic strategies for either reducing ß-cell proliferation in insulinomas or alleviating normal ß-cell deficiency in diabetes through the modulation of HLXB9 phosphorylation.
[Mh] Termos MeSH primário: Doenças do Sistema Endócrino/genética
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/metabolismo
Proteínas Associadas à Matriz Nuclear/genética
Proteínas Associadas à Matriz Nuclear/metabolismo
Fatores de Transcrição de Octâmero/genética
Fatores de Transcrição de Octâmero/metabolismo
Proteínas de Ligação a RNA/genética
Proteínas de Ligação a RNA/metabolismo
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Diabetes Mellitus/genética
Doenças do Sistema Endócrino/metabolismo
Mutação em Linhagem Germinativa
Seres Humanos
Recém-Nascido
Células Secretoras de Insulina/metabolismo
Células Secretoras de Insulina/patologia
Camundongos
Camundongos Transgênicos
Mutação
Ligação Proteica
Proteínas Proto-Oncogênicas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Nome de substância:
0 (Homeodomain Proteins); 0 (MNX1 protein, human); 0 (Men1 protein, mouse); 0 (NONO protein, human); 0 (Nuclear Matrix-Associated Proteins); 0 (Octamer Transcription Factors); 0 (Proto-Oncogene Proteins); 0 (RNA-Binding Proteins); 0 (Transcription Factors)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-03155


  10 / 8331 MEDLINE  
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[PMID]:29247589
[Au] Autor:Udagawa C; Nakamura H; Ohnishi H; Tamura K; Shimoi T; Yoshida M; Yoshida T; Totoki Y; Shibata T; Zembutsu H
[Ad] Endereço:Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
[Ti] Título:Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity.
[So] Source:Cancer Sci;109(2):446-452, 2018 Feb.
[Is] ISSN:1349-7006
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Although trastuzumab-induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify genetic variants determining the risk of trastuzumab-induced cardiotoxicity, we carried out whole exome sequencing of germline DNA samples from 9 patients with trastuzumab-induced cardiotoxicity, and conducted a case-control association study of 2258 genetic variants between 9 cases (with trastuzumab-induced cardiotoxicity) and general Japanese population controls registered in the Human Genetic Variation Database (HGVD). The top variant which showed the lowest P-value in the screening study was rs139503277 in PHD Finger Protein 3 (P = .00012, odds ratio [OR] = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing P < .001 in the screening study using 234 independent patients treated with trastuzumab, including 10 cases and 224 controls (without trastuzumab-induced cardiotoxicity). In the replication study, we observed that three variants had an effect in the same direction as in the screening study (rs78272919 in exon 2 of Keratin 15, rs5762940 in exon 2 of zinc and ring finger 3, and rs139944387 in exon 44 of Eyes shut homologs [EYS]). A combined result of the screening and the replication studies suggested an association of a locus on chromosome 6q12 with trastuzumab-induced cardiotoxicity (rs139944387 in EYS, combined P = .00056, OR = 13.73). This finding provides new insights into personalized trastuzumab therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive cancer.
[Mh] Termos MeSH primário: Cardiotoxicidade/genética
Marcadores Genéticos/genética
Polimorfismo de Nucleotídeo Único
Trastuzumab/toxicidade
Sequenciamento Completo do Exoma/métodos
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Estudos de Casos e Controles
Proteínas do Olho/genética
Feminino
Mutação em Linhagem Germinativa
Seres Humanos
Queratina-15/genética
Masculino
Meia-Idade
Fatores de Transcrição/genética
Ubiquitina-Proteína Ligases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EYS protein, human); 0 (Eye Proteins); 0 (Genetic Markers); 0 (KRT15 protein, human); 0 (Keratin-15); 0 (PHF3 protein, human); 0 (Transcription Factors); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.3.2.27 (ZNRF3 protein, human); P188ANX8CK (Trastuzumab)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE
[do] DOI:10.1111/cas.13471



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