RESUMO
Inflammation is a significant factor in cancer development, and a molecular understanding of the parameters dictating the impact of inflammation on cancers could significantly improve treatment. The tumor suppressor p53 is frequently mutated in cancer, and p53 missense mutants (mutp53) can acquire oncogenic properties. We report that cancer cells with mutp53 respond to inflammatory cytokines increasing their invasive behavior. Notably, this action is coupled to expression of chemokines that can expose the tumor to host immunity, potentially affecting response to therapy. Mechanistically, mutp53 fuels NF-κB activation while it dampens activation of ASK1/JNK by TNFα, and this action depends on mutp53 binding and inhibiting the tumor suppressor DAB2IP in the cytoplasm. Interfering with such interaction reduced aggressiveness of cancer cells in xenografts. This interaction is an unexplored mechanism by which mutant p53 can influence tumor evolution, with implications for our understanding of the complex role of inflammation in cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Citoplasma/metabolismo , Feminino , Células HCT116 , Humanos , Metástase Linfática , Neoplasias Mamárias Experimentais , Camundongos , Camundongos SCID , Mutação de Sentido IncorretoRESUMO
AIM: To introduce a questionnaire that can be used to assess the post-operative perception of the patients after palatal surgery. The questionnaire was named: Palate Post-Operative Problems Score (PPOPS). STUDY DESIGN: Pilot study. PATIENTS AND METHODS: The study was performed at Morgagni-Pierantoni hospital, Forli. Forty patients suffering from obstructive sleep apnea (OSA) who performed either expansion sphincter pharyngoplasty (ESP) or barbed reposition pharyngoplasty (BRP) in our hospital were divided into two groups, 20 patients per group. The patients' answers to the PPOPS questionnaire were recorded and their total scores were compared in addition to each item separately. PPOPS questionnaire consists of 12 items scored from 0 to 3 with a total score from 0 to 36. RESULTS: The overall average scores between both groups were similar being 4.05 for the BRP and 4.35 for the ESP with P value 0.4. From the results of the questionnaire, the patients favoured choosing BRP than ESP although some items showed better results among ESP patients and the difference between both techniques is not statistically significant. Every item score was separately compared and described in details later in the results. CONCLUSION: PPOPS questionnaire can be an additional useful tool for the assessment of any kind of palatal surgery through detailed analysis of the patients' perception for their surgery. BRP and ESP are similar procedures in the idea and results.
Assuntos
Procedimentos Cirúrgicos Otorrinolaringológicos , Preferência do Paciente , Satisfação do Paciente , Faringe/cirurgia , Apneia Obstrutiva do Sono/cirurgia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inquéritos e Questionários , Adulto JovemRESUMO
Primary myelofibrosis (PMF) is a Myeloproliferative Neoplasm (MPN) characterized by megakaryocyte hyperplasia, progressive bone marrow fibrosis, extramedullary hematopoiesis and transformation to Acute Myeloid Leukemia (AML). A number of phenotypic driver (JAK2, CALR, MPL) and additional subclonal mutations have been described in PMF, pointing to a complex genomic landscape. To discover novel genomic lesions that can contribute to disease phenotype and/or development, gene expression and copy number signals were integrated and several genomic abnormalities leading to a concordant alteration in gene expression levels were identified. In particular, copy number gain in the polyamine oxidase (PAOX) gene locus was accompanied by a coordinated transcriptional up-regulation in PMF patients. PAOX inhibition resulted in rapid cell death of PMF progenitor cells, while sparing normal cells, suggesting that PAOX inhibition could represent a therapeutic strategy to selectively target PMF cells without affecting normal hematopoietic cells' survival. Moreover, copy number loss in the chromatin modifier HMGXB4 gene correlates with a concomitant transcriptional down-regulation in PMF patients. Interestingly, silencing of HMGXB4 induces megakaryocyte differentiation, while inhibiting erythroid development, in human hematopoietic stem/progenitor cells. These results highlight a previously un-reported, yet potentially interesting role of HMGXB4 in the hematopoietic system and suggest that genomic and transcriptional imbalances of HMGXB4 could contribute to the aberrant expansion of the megakaryocytic lineage that characterizes PMF patients.
Assuntos
Dosagem de Genes , Proteína HMGB2/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Mielofibrose Primária/genética , Aberrações Cromossômicas , Eletroporação , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma , Poliamina OxidaseRESUMO
BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 81% of all cases of lung cancer and they are often fatal because 60% of the patients are diagnosed at an advanced stage. Besides the need for earlier diagnosis, there is a high need for additional effective therapies. In this work, we investigated the feasibility of a lung cancer progression mouse model, mimicking features of human aggressive NSCLC, as biological reservoir for potential therapeutic targets and biomarkers. RESULTS: We performed RNA-seq profiling on total RNA extracted from lungs of a 30 week-old K-ras(LA1)/p53(R172HΔg) and wild type (WT) mice to detect fusion genes and gene/exon-level differential expression associated to the increase of tumor mass. Fusion events were not detected in K-ras(LA1)/p53(R172HΔg) tumors. Differential expression at exon-level detected 33 genes with differential exon usage. Among them nine, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of more than 500 NSCLC RNA-seq transcriptomes. None of the genes showed a significant correlation between exon-level expression and disease prognosis. Differential expression at gene-level allowed the identification of 1513 genes with a significant increase in expression associated to tumor mass increase. 74 genes, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of two transcriptomics datasets of human NSCLC samples, encompassing more than 900 samples. SPP1 was the only molecule whose over-expression resulted statistically related to poor outcome regarding both survival and metastasis formation. Two other molecules showed over-expression associated to poor outcome due to metastasis formation: GM-CSF and ADORA3. GM-CSF is a secreted protein, and we confirmed its expression in the supernatant of a cell line derived by a K-ras(LA1)/p53(R172HΔg) mouse tumor. ADORA3 is instead involved in the induction of p53-mediated apoptosis in lung cancer cell lines. Since in our model p53 is inactivated, ADORA3 does not negatively affect tumor growth but remains expressed on tumor cells. Thus, it could represent an interesting target for the development of antibody-targeted therapy on a subset of NSCLC, which are p53 null and ADORA3 positive. CONCLUSIONS: Our study provided a complete transcription overview of the K-ras(LA1)/p53(R172HΔg) mouse NSCLC model. This approach allowed the detection of ADORA3 as a potential target for antibody-based therapy in p53 mutated tumors.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Animais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Genes p53 , Genes ras , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Osteopontina/genética , Prognóstico , Transcriptoma , Carga TumoralRESUMO
A great number of surgical diagnostic procedures are performed every year for thyroid nodules that are included in undetermined cytological classes that reveal to be malignant thyroid carcinomas in one-third of cases. In the most recent guidelines, lobectomy is the most recommended surgical approach for this classes of nodules, but total thyroidectomy is the recommended treatment for undetermined nodules larger than 4 cm. The main study aim is to support or question the dimensional criteria as an independent clinical decision element for undetermined thyroid nodules management. We examined data regarding 761 patients undergoing thyroid surgery for undetermined thyroid nodules at two high-volume endocrine surgery units in Italy. Patients were divided into three groups based on the preoperative size of the nodules (N < 1, 1 < N < 4, N > 4 cm). Among the patients belonging to the different groups, we analyzed: differences in malignancy rate, histological characteristics of invasiveness and neoplastic aggressiveness, rates of recurrence and response to therapy. Nodule size (evaluated as a categorical variable and as a continuous variable) did not show any statistically significant correlation with the rate of malignancy, histopathological characteristics of tumor aggressiveness and the patient's clinical outcome. Most of the tumors found were included in the low risk class (79.2%) and only one was classified as high risk. Follow up of cancer cases showed excellent results in terms of survival, response to therapy and disease recurrence. Malignant thyroid tumors of any size resulting from a nodule identified as cytologically indeterminate are usually characterized by a low risk follicular pattern, well-differentiated and with an excellent outcome. As a result, preferring an extended surgical attitude for undetermined nodules based on tumor size, in absence of other risk factors, can lead to overtreatment in a significant percentage of cases.
Assuntos
Adenocarcinoma Folicular , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Adenocarcinoma Folicular/cirurgia , Biópsia por Agulha Fina , Humanos , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/cirurgia , TireoidectomiaRESUMO
The identification of the site in head neck unknown primary (HNUP) tumour is of utmost importance to help select best treatment while decreasing treatment-related morbidity and mortality. The primary purpose of this study is to demonstrate that TORS may be a valuable tool in detecting primary tumour. Studies were systematically searched in the PubMed, EMBASE, the Cochrane Library and CENTRAL electronic databases. A total of 12 selected studies (349 patients) were analyzed. The primary tumour detection and positive surgical margins rates were 70.8% and 19.4%, respectively. The rate of HPV-related tumour was 71.3%. The primary tumour was mainly in base of tongue (64%). In conclusion, TORS seems to be an effective surgical approach both in terms of detection of primary tumour site and in terms of therapeutic perspective for HNUP. In particular, a subset of HPV-related tumours might benefits all advantages from this surgical modality.
Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico , Linfonodos/patologia , Neoplasias Primárias Desconhecidas/diagnóstico , Infecções por Papillomavirus/diagnóstico , Procedimentos Cirúrgicos Robóticos/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/secundário , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Pescoço , Neoplasias Primárias Desconhecidas/cirurgia , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/cirurgia , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Neoplasias da Língua/diagnóstico , Neoplasias da Língua/patologia , Neoplasias da Língua/cirurgiaRESUMO
BACKGROUND: Owing to the complex processes required for anthracycline-induced cytotoxicity, a prospectively defined multifactorial Consensus Signature (ConSig) might improve prediction of anthracycline response in triple-negative breast cancer (TNBC) patients, whose only standard systemic treatment option is chemotherapy. AIMS: We aimed to construct and evaluate a multifactorial signature, comprising measures of each function required for anthracycline sensitivity in TNBC. METHODS: ConSigs were constructed based on five steps required for anthracycline function: drug penetration, nuclear topoisomerase IIα (topoIIα) protein location, increased topoIIα messenger RNA (mRNA) expression, apoptosis induction, and immune activation measured by, respectively, HIF1α or SHARP1 signature, LAPTM4B mRNA, topoIIα mRNA, Minimal Gene signature or YWHAZ mRNA, and STAT1 signature. TNBC patients treated with neoadjuvant anthracycline-based chemotherapy without taxane were identified from publicly available gene expression data derived with Affymetrix HG-U133 arrays (training set). In silico analyses of correlation between gene expression data and pathological complete response (pCR) were performed using receiver-operating characteristic curves. To determine anthracycline specificity, ConSigs were assessed in patients treated with anthracycline plus taxane. Specificity, sensitivity, positive and negative predictive value, and odds ratio (OR) were calculated for ConSigs. Analyses were repeated in two validation gene expression data sets derived using different microarray platforms. RESULTS: In the training set, 29 of 147 patients had pCR after anthracycline-based chemotherapy. Various combinations of components were evaluated, with the most powerful anthracycline response predictors being ConSig1: (STAT1+topoIIα mRNA+LAPTM4B) and ConSig2: (STAT1+topoIIα mRNA+HIF1α). ConSig1 demonstrated high negative predictive value (85%) and high OR for no pCR (3.18) and outperformed ConSig2 in validation sets for anthracycline specificity. CONCLUSIONS: With further validation, ConSig1 may help refine selection of TNBC patients for anthracycline chemotherapy.
RESUMO
Mammary epithelial stem cells are fundamental to maintain tissue integrity. Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. Here we show that both normal stem cells and CSCs of the breast are controlled by the prolyl-isomerase Pin1. Mechanistically, following interaction with Pin1, Notch1 and Notch4, key regulators of cell fate, escape from proteasomal degradation by their major ubiquitin-ligase Fbxw7α. Functionally, we show that Fbxw7α acts as an essential negative regulator of breast CSCs' expansion by restraining Notch activity, but the establishment of a Notch/Pin1 active circuitry opposes this effect, thus promoting breast CSCs self-renewal, tumor growth and metastasis in vivo. In human breast cancers, despite Fbxw7α expression, high levels of Pin1 sustain Notch signaling, which correlates with poor prognosis. Suppression of Pin1 holds promise in reverting aggressive phenotypes, through CSC exhaustion as well as recovered drug sensitivity carrying relevant implications for therapy of breast cancers.
Assuntos
Neoplasias da Mama/metabolismo , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Peptidilprolil Isomerase/metabolismo , Células-Tronco/metabolismo , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Proteína 7 com Repetições F-Box-WD , Feminino , Humanos , Glândulas Mamárias Humanas/citologia , Camundongos , Camundongos Knockout , Camundongos SCID , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/antagonistas & inibidores , Peptidilprolil Isomerase/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptor Notch4 , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais , Células-Tronco/citologia , Transplante Heterólogo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
PURPOSE: This is a randomized, double-blind, placebo-controlled study aimed to evaluate the clinical and biologic effects of letrozole plus lapatinib or placebo as neoadjuvant therapy in hormone receptor (HR) -positive/human epidermal growth factor receptor 2 (HER2) -negative operable breast cancer. METHODS: Ninety-two postmenopausal women with stage II to IIIA primary breast cancer were randomly assigned to preoperative therapy consisting of 6 months of letrozole 2.5 mg orally daily plus lapatinib 1,500 mg orally daily or placebo. Surgery was performed within 2 weeks from the last study medication. Clinical response was assessed by ultrasonography. Pre- and post-treatment samples were evaluated for selected biomarkers. Fresh-frozen tissue samples were collected for genomic analyses. RESULTS: Numerically similar clinical response rates (partial + complete response) were observed (70% for letrozole-lapatinib and 63% for letrozole-placebo). Toxicities were generally mild and manageable. A significant decrease in Ki-67 and pAKT expression from baseline to surgery was observed in both arms. Overall, 34 patients (37%) had a mutation in PIK3CA exon 9 or 20. In the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the presence of PIK3CA mutation (objective response rate, 93% v 63% in PIK3CA wild type; P = .040). CONCLUSION: The combination of letrozole-lapatinib in early breast cancer was feasible, with expected and manageable toxicities. In unselected estrogen receptor-positive/HER2-negative patients, letrozole-lapatinib and letrozole-placebo resulted in a similar overall clinical response rate and similar effect on Ki-67 and pAKT. Our secondary end point findings of a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in HR-positive/HER2-negative early breast cancer must now be independently confirmed.