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1.
Microrna ; 6(1): 53-70, 2017.
Article in English | MEDLINE | ID: mdl-27897122

ABSTRACT

BACKGROUND: The goal of this project was to characterize the molecular and cellular roles of various gene targets regulated by miRNAs identified in differentiating and stimulating avian macrophages. Once a monocyte arrives to a site of infection, local signals induce a redistribution of resources into a macrophage phenotype. This may involve upregulating pathogen pattern recognizing receptors and increasing the efficiency of lysosomal biogenesis, while simultaneously recycling components involved in circulatory migration and leukocyte extravasation. a monocyte tooled with chemokine surface receptors and an internal cytoskeletal structure geared towards mobility may efficiently sense, react, and migrate toward a site of infection. METHODS: Peripheral blood derived monocytes were purified and cultured from young chickens. RNA sequencing was performed on both peripheral blood monocytes during differentiation into macrophages and on mature macrophages following stimulation with interferon gamma. A set of microRNAs were identified and investigated using bioinformatics methods to ascertain their potential role in avian macrophage biology. RESULTS: Among a number of miRNAs that are found to be expressed in avian macrophages, we focused on eight specific miRNAs (miR-1618, miR-1586, miR-1633, miR-1627, miR-1646, miR-1649, miR-1610, miR-1647) associated with macrophage differentiation and activation. Expression profiles of microRNAs were characterized during differentiation and activation. Candidate miRNA targets were implicated in processes including Wnt signaling, ubiquitination, PPAR mediated macrophage function, vesicle mediated cytokine trafficking, and WD40 domain protein functions. CONCLUSION: A global theme for macrophage function that may be modulated by microRNAs is the comprehensive redistribution of the cell's protein repertoire. This redistribution involves two processes: 1) the degradation and recycling of unneeded cytoplasmic and membrane components and 2) the mobilization of newly synthesized cellular components via vesicular trafficking. Generally, it appears that macrophages need to closely regulate gene expression for differentiation to be able to activate successfully in response to a pathogen. This is a process in which miRNAs participate by affecting several pathways critical for both, differentiation and activation.


Subject(s)
Cell Differentiation/genetics , Computational Biology , Macrophage Activation/genetics , Macrophages/cytology , Macrophages/metabolism , MicroRNAs/genetics , Monocytes/cytology , Monocytes/metabolism , Animals , Cells, Cultured , Chickens , Computational Biology/methods , Cytokines/metabolism , Gene Expression Profiling , Gene Expression Regulation/drug effects , Interferon-gamma/immunology , Interferon-gamma/pharmacology , Macrophage Activation/drug effects , Macrophage Activation/immunology , Macrophages/immunology , Monocytes/immunology , Multigene Family , Peroxisome Proliferator-Activated Receptors/metabolism , RNA Interference , Transport Vesicles/metabolism , Ubiquitin/metabolism , WD40 Repeats , Wnt Signaling Pathway/drug effects
2.
Int J Radiat Oncol Biol Phys ; 95(4): 1117-31, 2016 07 15.
Article in English | MEDLINE | ID: mdl-27354127

ABSTRACT

PURPOSE: To review our 15-year institutional experience using intensity modulated radiation therapy (IMRT) to reirradiate patients with head and neck squamous cell carcinomas (HNSCC) and identify predictors of outcomes and toxicity. METHODS AND MATERIALS: We retrospectively reviewed the records of 227 patients who received head and neck reirradiation using IMRT from 1999 to 2014. Patients treated with noncurative intent were excluded. Radiation-related acute and late toxicities were recorded. Prognostic variables included performance status, disease site, disease-free interval, chemotherapy, and RT dose and volume. Correlative analyses were performed separately for surgery and nonsurgery patients. RESULTS: Two hundred six patients (91%) were retreated with curative intent, and 173 had HNSCC histology; 104 (50%) underwent salvage resection, and 135 (66%) received chemotherapy. Median follow-up after reirradiation was 24.7 months. Clinical outcomes were worse for HNSCC patients, with 5-year locoregional control, progression-free survival, and overall survival rates of 53%, 22%, and 32%, respectively, compared with 74%, 59%, and 79%, respectively, for non-HNSCC patients. On multivariate analysis, concurrent chemotherapy and retreatment site were associated with tumor control, whereas performance status was associated with survival. Favorable prognostic factors specific to surgery patients were neck retreatment and lack of extracapsular extension, whereas for nonsurgery patients, these were a nasopharynx subsite and complete response to induction chemotherapy. Actuarial rates of grade ≥3 toxicity were 32% at 2 years and 48% at 5 years, with dysphagia or odynophagia being most common. Increased grade ≥3 toxicity was associated with retreatment volume >50 cm(3) and concurrent chemotherapy. CONCLUSIONS: Reirradiation with IMRT either definitively or after salvage surgery can produce promising local control and survival in selected patients with head and neck cancers. Treatment-related toxicity remains significant. Prognostic factors are emerging to guide multidisciplinary treatment approaches and clinical trial design.


Subject(s)
Carcinoma, Squamous Cell/radiotherapy , Head and Neck Neoplasms/radiotherapy , Radiotherapy, Intensity-Modulated/methods , Re-Irradiation , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/mortality , Disease-Free Survival , Female , Head and Neck Neoplasms/mortality , Humans , Male , Middle Aged , Radiotherapy, Intensity-Modulated/adverse effects , Retrospective Studies , Salvage Therapy , Squamous Cell Carcinoma of Head and Neck
3.
Int J Radiat Oncol Biol Phys ; 96(1): 30-41, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27325480

ABSTRACT

PURPOSE: Reirradiation of head and neck (H&N) cancer is a clinical challenge. Proton radiation therapy (PRT) offers dosimetric advantages for normal tissue sparing and may benefit previously irradiated patients. Here, we report our initial experience with the use of PRT for H&N reirradiation, with focus on clinical outcomes and toxicity. METHODS AND MATERIALS: We retrospectively reviewed the records of patients who received H&N reirradiation with PRT from April 2011 through June 2015. Patients reirradiated with palliative intent or without prior documentation of H&N radiation therapy were excluded. Radiation-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events Version 4.0. RESULTS: The conditions of 60 patients were evaluated, with a median follow-up time of 13.6 months. Fifteen patients (25%) received passive scatter proton therapy (PSPT), and 45 (75%) received intensity modulated proton therapy (IMPT). Thirty-five patients (58%) received upfront surgery, and 44 (73%) received concurrent chemotherapy. The 1-year rates of locoregional failure-free survival, overall survival, progression-free survival, and distant metastasis-free survival were 68.4%, 83.8%, 60.1%, and 74.9%, respectively. Eighteen patients (30%) experienced acute grade 3 (G3) toxicity, and 13 (22%) required a feeding tube at the end of PRT. The 1-year rates of late G3 toxicity and feeding tube independence were 16.7% and 2.0%, respectively. Three patients may have died of reirradiation-related effects (1 acute and 2 late). CONCLUSIONS: Proton beam therapy can be a safe and effective curative reirradiation strategy, with acceptable rates of toxicity and durable disease control.


Subject(s)
Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/therapy , Neoplasm Recurrence, Local/mortality , Proton Therapy/mortality , Radiation Injuries/mortality , Re-Irradiation/mortality , Adult , Aged , Causality , Combined Modality Therapy/mortality , Combined Modality Therapy/statistics & numerical data , Comorbidity , Disease-Free Survival , Female , Follow-Up Studies , Humans , Longitudinal Studies , Male , Middle Aged , Neoplasm Recurrence, Local/prevention & control , Palliative Care/statistics & numerical data , Prevalence , Prognosis , Proton Therapy/statistics & numerical data , Radiation Injuries/prevention & control , Radiotherapy, Conformal/mortality , Radiotherapy, Conformal/statistics & numerical data , Re-Irradiation/statistics & numerical data , Retrospective Studies , Risk Factors , Survival Analysis , Texas/epidemiology , Treatment Outcome
4.
Head Neck ; 38 Suppl 1: E580-7, 2016 04.
Article in English | MEDLINE | ID: mdl-25782700

ABSTRACT

BACKGROUND: The purpose of this study was to assess outcomes of patients with orbital carcinomas treated with orbital exenteration and intensity-modulated radiation therapy (IMRT). METHODS: Twenty-nine patients were treated with orbital exenteration and postoperative IMRT between 2002 through 2011; their medical records were retrospectively reviewed. RESULTS: Adenoid cystic carcinoma represented the most common histology (41%) followed by squamous cell carcinoma (21%). Perineural invasion (PNI) was identified in 22 patients (76%). The median radiation dose was 60 Gy (range, 60-70). Seven patients (24%) received neck radiation. The median follow-up was 43 months (range, 5-102 months). Five-year local control, overall survival (OS), and disease-free survival rates were 83%, 60%, and 55%, respectively. PNI (p = .01) and especially involvement of a named nerve (p = .001) significantly correlated with worse OS. CONCLUSION: Favorable disease control rates for orbital carcinomas are achievable with IMRT after orbital exenteration even for patients with advanced disease. Toxicity for the contralateral eye was minimal. © 2015 Wiley Periodicals, Inc. Head Neck 38: E580-E587, 2016.


Subject(s)
Carcinoma, Adenoid Cystic/radiotherapy , Carcinoma, Squamous Cell/radiotherapy , Orbital Neoplasms/radiotherapy , Radiotherapy, Intensity-Modulated , Disease-Free Survival , Female , Humans , Male , Middle Aged , Retrospective Studies , Survival Rate
5.
Head Neck ; 38 Suppl 1: E1459-66, 2016 04.
Article in English | MEDLINE | ID: mdl-26560893

ABSTRACT

BACKGROUND: Overexpression of p16 is associated with improved outcomes among patients with oropharyngeal carcinoma. However, its role in the outcomes of patients with nasopharyngeal cancer (NPC) remains unclear. METHODS: Eighty-six patients with NPC treated at MD Anderson Cancer Center from 2000 to 2014 were identified. Epstein-Barr virus (EBV) and human papillomavirus (HPV) status were determined by in situ hybridization (ISH) and p16 by immunohistochemical staining. RESULTS: EBV positivity was associated with extended overall survival (OS; median, 95.0 vs 44.9 months; p < .004), progression-free survival (PFS; median, 80.4 vs 28.1 months; p < .013), and locoregional control (median, 104.4 vs 65.5 months; p < .043). In patients with EBV-positive tumors, p16 overexpression correlated with improved PFS (median, 106.3 vs 27.1 months; p < .02) and locoregional control (median, 93.6 vs 64.5 months; p < .02). CONCLUSION: P16 overexpression is associated with improved PFS and locoregional control in patients with EBV-positive NPC. P16 expression may complement EBV status in predicting treatment outcomes for patients with NPC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1459-E1466, 2016.


Subject(s)
Carcinoma/diagnosis , Carcinoma/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Epstein-Barr Virus Infections/metabolism , Nasopharyngeal Neoplasms/diagnosis , Nasopharyngeal Neoplasms/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma/virology , Disease Progression , Disease-Free Survival , Female , Herpesvirus 4, Human , Humans , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/virology , Prognosis , Retrospective Studies , Young Adult
6.
Head Neck ; 38 Suppl 1: E925-33, 2016 04.
Article in English | MEDLINE | ID: mdl-25994561

ABSTRACT

BACKGROUND: Treatment of T4 nasopharyngeal carcinoma (NPC) is challenging because of the proximity of the tumor to the central nervous system. The purpose of this study was to present our evaluation of disease control and toxicity outcomes for patients with T4 NPC treated with intensity-modulated radiation therapy (IMRT) and chemotherapy. METHODS: The medical records of 66 patients with T4 NPC treated from 2002 to 2012 with IMRT were reviewed. Endpoints included tumor control and toxicity outcomes (Common Terminology Criteria for Adverse Events [CTCAE v4.0]). RESULTS: Median follow-up was 38 months. Five-year rates of locoregional control, distant metastasis-free survival, progression-free survival (PFS), and overall survival (OS) were 80%, 62%, 57%, and 69%, respectively. Nodal involvement was associated with worse PFS (p = .015). Gross target volume (GTV) volume >100 cm and planning target volume (PTV) volume >400 cm were associated with worse OS (p = .038 and p = .004, respectively). Four patients had significant cognitive impairment, and 9 had MRI evidence of brain necrosis. CONCLUSION: For patients with T4 NPC treated with IMRT and chemotherapy, survival and locoregional disease control rates have improved; however, late treatment toxicity remains a concern. © 2015 Wiley Periodicals, Inc. Head Neck 38: E925-E933, 2016.


Subject(s)
Carcinoma/radiotherapy , Nasopharyngeal Neoplasms/radiotherapy , Radiotherapy, Intensity-Modulated , Adolescent , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Male , Middle Aged , Radiotherapy Dosage , Radiotherapy, Intensity-Modulated/adverse effects , Retrospective Studies , Survival Rate , Young Adult
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