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1.
Mod Pathol ; 33(2): 228-234, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31383968

RESUMO

Asbestos describes a group of naturally occurring fibrous silicate mineral compounds that have been associated with a number of respiratory maladies, including mesothelioma and lung cancer. In addition, based primarily on epidemiologic studies, asbestos has been implicated as a risk factor for laryngeal and pharyngeal squamous cell carcinoma (SCC). The main objective of this work was to strengthen existing evidence via empirical demonstration of persistent asbestos fibers embedded in the tissue surrounding laryngeal and pharyngeal SCC, thus providing a more definitive biological link between exposure and disease. Six human papillomavirus (HPV)-negative laryngeal (n = 4) and pharyngeal (n = 2) SCC cases with a history working in an asbestos-exposed occupation were selected from a large population-based case-control study of head and neck cancer. A laryngeal SCC case with no history of occupational asbestos exposure was included as a control. Tissue cores were obtained from adjacent nonneoplastic tissue in tumor blocks from the initial primary tumor resection, and mineral fiber analysis was performed using a scanning electron microscope equipped with an energy dispersive X-ray analyzer (EDXA). Chrysotile asbestos fiber bundles were identified in 3/6 of evaluated cases with a history of occupational asbestos exposure. All three cases had tumors originating in the larynx. In addition, a wollastonite fiber of unclear significance was identified one of the HPV-negative pharyngeal SCC cases. No mineral fibers were identified in adjacent tissue of the case without occupational exposure. The presence of asbestos fibers in the epithelial tissue surrounding laryngeal SCC in cases with a history of occupational asbestos exposure adds a key line of physical evidence implicating asbestos as an etiologic factor.


Assuntos
Asbestos Serpentinas/efeitos adversos , Neoplasias Laríngeas/etiologia , Exposição Ocupacional/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Idoso , Asbestos Serpentinas/análise , Estudos de Casos e Controles , Células Epiteliais/química , Células Epiteliais/ultraestrutura , Humanos , Neoplasias Laríngeas/química , Neoplasias Laríngeas/ultraestrutura , Laringe/química , Laringe/ultraestrutura , Masculino , Pessoa de Meia-Idade , Fibras Minerais/efeitos adversos , Fibras Minerais/análise , Medição de Risco , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Carcinoma de Células Escamosas de Cabeça e Pescoço/ultraestrutura
2.
Am J Pathol ; 189(11): 2221-2232, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31472109

RESUMO

Recent evidence has demonstrated that reactive oxygen (eg, hydrogen peroxide) can activate host cell signaling pathways that function in repair. We show that mice deficient in their capacity to generate reactive oxygen by the NADPH oxidase 2 holoenzyme, an enzyme complex highly expressed in neutrophils and macrophages, have disrupted capacity to orchestrate signaling events that function in mucosal repair. Similar observations were made for mice after neutrophil depletion, pinpointing this cell type as the source of the reactive oxygen driving oxidation-reduction protein signaling in the epithelium. To simulate epithelial exposure to high levels of reactive oxygen produced by neutrophils and gain new insight into this oxidation-reduction signaling, epithelial cells were treated with hydrogen peroxide, biochemical experiments were conducted, and a proteome-wide screen was performed using isotope-coded affinity tags to detect proteins oxidized after exposure. This analysis implicated signaling pathways regulating focal adhesions, cell junctions, and maintenance of the cytoskeleton. These pathways are also known to act via coordinated phosphorylation events within proteins that constitute the focal adhesion complex, including focal adhesion kinase and Crk-associated substrate. We identified the Rho family small GTP-binding protein Ras-related C3 botulinum toxin substrate 1 and p21 activated kinases 2 as operational in these signaling and localization pathways. These data support the hypothesis that reactive oxygen species from neutrophils can orchestrate epithelial cell-signaling events functioning in intestinal repair.


Assuntos
Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Intestinos/lesões , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Células Cultivadas , Células Epiteliais/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiologia , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2/genética , Espécies Reativas de Oxigênio/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Cicatrização/fisiologia
3.
Am J Pathol ; 188(4): 937-949, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29366677

RESUMO

Several proteins endogenously produced during the process of intestinal wound healing have demonstrated prorestitutive properties. The presence of serum amyloid A1 (SAA1), an acute-phase reactant, within inflamed tissues, where it exerts chemotaxis of phagocytes, is well recognized; however, a putative role in intestinal wound repair has not been described. Herein, we show that SAA1 induces intestinal epithelial cell migration, spreading, and attachment through a formyl peptide receptor 2-dependent mechanism. Induction of the prorestitutive phenotype is concentration and time dependent and is associated with epithelial reactive oxygen species production and alterations in p130 Crk-associated substrate staining. In addition, using a murine model of wound recovery, we provide evidence that SAA1 is dynamically and temporally regulated, and that the elaboration of SAA1 within the wound microenvironment correlates with the influx of SAA1/CD11b coexpressing immune cells and increases in cytokines known to induce SAA expression. Overall, the present work demonstrates an important role for SAA in epithelial wound recovery and provides evidence for a physiological role in the wound environment.


Assuntos
Células Epiteliais/metabolismo , Proteína Amiloide A Sérica/metabolismo , Animais , Células CACO-2 , Adesão Celular , Movimento Celular , Proteína Substrato Associada a Crk/metabolismo , Citocinas/metabolismo , Células Epiteliais/patologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Receptores de Formil Peptídeo/metabolismo , Transdução de Sinais , Cicatrização
4.
Proc Natl Acad Sci U S A ; 113(51): 14787-14792, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27930307

RESUMO

Inflammatory bowel disease (IBD) results from aberrant immune stimulation against a dysbiotic mucosal but relatively preserved luminal microbiota and preferentially affects males in early onset disease. However, factors contributing to sex-specific risk and the pattern of dysbiosis are largely unexplored. Core 1 ß3GalT-specific molecular chaperone (Cosmc), which encodes an X-linked chaperone important for glycocalyx formation, was recently identified as an IBD risk factor by genome-wide association study. We deleted Cosmc in mouse intestinal epithelial cells (IECs) and found marked reduction of microbiota diversity in progression from the proximal to the distal gut mucosa, but not in the overlying lumen, as seen in IBD. This loss of diversity coincided with local emergence of a proinflammatory pathobiont and distal gut restricted pathology. Mechanistically, we found that Cosmc regulates host genes, bacterial ligands, and nutrient availability to control microbiota biogeography. Loss of one Cosmc allele in males (IEC-Cosmc-/y) resulted in a compromised mucus layer, spontaneous microbe-dependent inflammation, and enhanced experimental colitis; however, females with loss of one allele and mosaic deletion of Cosmc in 50% of crypts (IEC-Cosmc+/-) were protected from spontaneous inflammation and partially protected from experimental colitis, likely due to lateral migration of normal mucin glycocalyx from WT cells over KO crypts. These studies functionally validate Cosmc as an IBD risk factor and implicate it in regulating the spatial pattern of dysbiosis and sex bias in IBD.


Assuntos
Microbioma Gastrointestinal , Genes Ligados ao Cromossomo X , Doenças Inflamatórias Intestinais/genética , Chaperonas Moleculares/genética , Fatores Sexuais , Alelos , Animais , Colite/microbiologia , Feminino , Deleção de Genes , Ligação Genética , Estudo de Associação Genômica Ampla , Glicocálix , Inflamação , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mosaicismo , Fatores de Risco , Cromossomo X
5.
Pathol Res Pract ; 261: 155486, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39088875

RESUMO

High-risk human papillomavirus (hrHPV) is an emerging risk factor for sinonasal squamous cell carcinoma (SNSCC). The goal of this study was to assess the prevalence of hrHPV and subtype distribution in SNSCC and correlation with patient and clinical characteristics. This retrospective cohort study included 43 cases diagnosed with incident primary SNSCC at the University of Cincinnati Medical Center from 2010 to 2015. The prevalence of hrHPV was interrogated using a multi-assay approach that included p16 immunohistochemistry (IHC), RNA in-situ hybridization (ISH), and hrHPV DNA sequencing. The association of hrHPV with 5-year overall survival (OS) and 2-year disease-free survival (DFS) was assessed. Fourteen cases (32.6 %) were classified as hrHPV positive, based on the a priori definition of having either a positive RNAScope™ ISH test or hrHPV DNA and p16-positive IHC; 9 cases (20.9 %) were positive for all three tests. All cases that arose from an inverted sinonasal papilloma (ex-ISP) were negative for hrHPV. HPV16 was the most common subtype among hrHPV positive cases (58.8 %), followed by HPV18 (17.6 %). No significant association was observed between hrHPV and OS or DFS after adjusting for potential confounding. hrHPV is prevalent in a sizable fraction of SNSCC. Additional studies are needed to better elucidate the relationship with patient survival outcomes and determine the optimal testing modality for prognostication.


Assuntos
Papillomavirus Humano , Infecções por Papillomavirus , Neoplasias dos Seios Paranasais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Papillomavirus Humano/genética , Papillomavirus Humano/isolamento & purificação , Imuno-Histoquímica , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Neoplasias dos Seios Paranasais/mortalidade , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/virologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
6.
Clin Cancer Res ; 28(16): 3464-3472, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35653116

RESUMO

PURPOSE: Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection. PATIENTS AND METHODS: This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery. RESULTS: Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8-88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58-91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)-positive and PD-L1-negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083). CONCLUSIONS: Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Antígeno B7-H1 , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/patologia , Nivolumabe/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia
7.
Clin Cancer Res ; 28(7): 1345-1352, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35338369

RESUMO

PURPOSE: Patients with resected, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%-69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear. PATIENTS AND METHODS: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1-3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60-66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0. RESULTS: From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27-80), 30% were female, 86% had stage T3-T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%-90%) in the intermediate-risk group and 66% (95% CI, 55%-84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%-77%). No new safety signals were identified. CONCLUSIONS: Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Quimioterapia Adjuvante , Cisplatino/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
8.
Case Rep Oncol Med ; 2020: 8814871, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133711

RESUMO

Rosai-Dorfman disease (RDD), or sinus histiocytosis with massive lymphadenopathy, is a rare non-Langerhans cell histiocytosis. We report a case of a 69-year-old male with concurrent appendiceal and rectal masses who underwent CT-guided percutaneous biopsy. Histopathology confirmed a diagnosis of RDD with IgG4-positive plasma cells. It is believed to be a subset of RDD that shares similar features with IgG4-related disease suggesting some overlap of the two diseases. Because gastrointestinal RDD accounts for less than 1% of extranodal disease, it is important to recognize this entity in order to guide management. We review the presentation, diagnosis, and treatment of gastrointestinal RDD and discuss the possible overlap with IgG4-related disease.

9.
J Immunother Cancer ; 8(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33060146

RESUMO

BACKGROUND: Immunotherapy has emerged as a promising treatment modality for head and neck squamous cell carcinoma (HNSCC). Pembrolizumab, an anti-programmed death 1 antibody, is an immunotherapy agent currently approved for metastatic HNSCC and curative intent clinical trials. Although clinical responses to pembrolizumab are promising, many patients fail to respond. However, it is well known that T cell cytotoxicity and chemotaxis are critically important in the elimination of HNSCC tumors. These functions depend on ion channel activity and downstream Ca2+ fluxing abilities, which are defective in patients with HNSCC. The purpose of this study was to elucidate the effects of pembrolizumab on potassium (K+) channel (KCa3.1 and Kv1.3) activity, Ca2+ fluxes, and chemotaxis in the cytotoxic T cells of patients with HNSCC and to determine their correlation with treatment response. METHODS: Functional studies were conducted in CD8+ peripheral blood T cells (PBTs) and tumor infiltrating lymphocytes (TILs) from patients with HNSCC treated with pembrolizumab. Untreated patients with HNSCC were used as controls. The ion channel activity of CD8+ T cells was measured by patch-clamp electrophysiology; single-cell Ca2+ fluxing abilities were measured by live microscopy. Chemotaxis experiments were conducted in a three-dimensional collagen matrix. Pembrolizumab patients were stratified as responders or non-responders based on pathological response (percent of viable tumor remaining at resection; responders: ≤80% viable tumor; non-responders: >80% viable tumor). RESULTS: Pembrolizumab increased K+ channel activity and Ca2+ fluxes in TILs independently of treatment response. However, in PBTs from responder patients there was an increased KCa3.1 activity immediately after pembrolizumab treatment that was accompanied by a characteristic increase in Kv1.3 and Ca2+ fluxes as compared with PBTs from non-responder patients. The effects on Kv1.3 and Ca2+ were prolonged and persisted after tumor resection. Chemotaxis was also improved in responder patients' PBTs. Unlike non-responders' PBTs, pembrolizumab increased their ability to chemotax in a tumor-like, adenosine-rich microenvironment immediately after treatment, and additionally they maintained an efficient chemotaxis after tumor resection. CONCLUSIONS: Pembrolizumab enhanced K+ channel activity, Ca2+ fluxes and chemotaxis of CD8+ T cells in patients with HNSCC, with a unique pattern of response in responder patients that is conducive to the heightened functionality of their cytotoxic T cells.


Assuntos
Cálcio/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Imunoterapia/métodos , Potássio/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Citotóxicos/metabolismo , Idoso , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais
10.
Am J Surg ; 218(4): 730-736, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31399195

RESUMO

BACKGROUND: We determined the sampling error rate of flat epithelial atypia (FEA) and evaluated current guidelines recommending excisional biopsy. METHODS: A retrospective review of consecutive excisional biopsies after image-guided core-needle biopsy identified patients with isolated FEA diagnosed between 2014 and 2018. Clinical and pathologic parameters were evaluated. RESULTS: Twenty-five women with 27 biopsies were included. Based on pathologic review of original core specimens, 44.4% (N = 12) were accurately diagnosed as FEA. Upon excision, lesions were upgraded to ductal carcinoma in situ (N = 2) or invasive ductal carcinoma (N = 1) in 11.1% of cases. Older age, black race, hormone replacement, and calcifications in the image-guided biopsy specimen were associated with the presence of high-risk or malignant lesions in the excisional biopsy (all p ≤ 0.05). CONCLUSIONS: In this study, FEA was frequently overcalled. However, lesions suspicious for FEA warrant excision due to their association with malignancy or high-risk lesions, which may necessitate further surgical management and/or risk-reducing strategies.


Assuntos
Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/patologia , Carcinoma/patologia , Células Epiteliais/patologia , Biópsia Guiada por Imagem , Neoplasias da Mama/cirurgia , Carcinoma/cirurgia , Feminino , Humanos , Hiperplasia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Viés de Seleção
11.
Redox Biol ; 20: 526-532, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30508697

RESUMO

Intestinal homeostasis is regulated in-part by reactive oxygen species (ROS) that are generated in the colonic mucosa following contact with certain lactobacilli. Mechanistically, ROS can modulate protein function through the oxidation of cysteine residues within proteins. Recent advances in cysteine labeling by the Isotope Coded Affinity Tags (ICATs) technique has facilitated the identification of cysteine thiol modifications in response to stimuli. Here, we used ICATs to map the redox protein network oxidized upon initial contact of the colonic mucosa with Lactobacillus rhamnosus GG (LGG). We detected significant LGG-specific redox changes in over 450 proteins, many of which are implicated to function in cellular processes such as endosomal trafficking, epithelial cell junctions, barrier integrity, and cytoskeleton maintenance and formation. We particularly noted the LGG-specific oxidation of Rac1, which is a pleiotropic regulator of many cellular processes. Together, these data reveal new insights into lactobacilli-induced and redox-dependent networks involved in intestinal homeostasis.


Assuntos
Mucosa Intestinal/metabolismo , Oxirredução , Proteoma , Proteômica , Transdução de Sinais , Linhagem Celular , Biologia Computacional/métodos , Modelos Biológicos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Massas em Tandem
13.
Cell Mol Gastroenterol Hepatol ; 5(4): 499-522, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29930976

RESUMO

BACKGROUND & AIMS: Ileal bile acid absorption is mediated by uptake via the apical sodium-dependent bile acid transporter (ASBT), and export via the basolateral heteromeric organic solute transporter α-ß (OSTα-OSTß). In this study, we investigated the cytotoxic effects of enterocyte bile acid stasis in Ostα-/- mice, including the temporal relationship between intestinal injury and initiation of the enterohepatic circulation of bile acids. METHODS: Ileal tissue morphometry, histology, markers of cell proliferation, gene, and protein expression were analyzed in male and female wild-type and Ostα-/- mice at postnatal days 5, 10, 15, 20, and 30. Ostα-/-Asbt-/- mice were generated and analyzed. Bile acid activation of intestinal Nrf2-activated pathways was investigated in Drosophila. RESULTS: As early as day 5, Ostα-/- mice showed significantly increased ileal weight per length, decreased villus height, and increased epithelial cell proliferation. This correlated with premature expression of the Asbt and induction of bile acid-activated farnesoid X receptor target genes in neonatal Ostα-/- mice. Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase-1 and Nrf2-anti-oxidant responsive genes were increased significantly in neonatal Ostα-/- mice at these postnatal time points. Bile acids also activated Nrf2 in Drosophila enterocytes and enterocyte-specific knockdown of Nrf2 increased sensitivity of flies to bile acid-induced toxicity. Inactivation of the Asbt prevented the changes in ileal morphology and induction of anti-oxidant response genes in Ostα-/- mice. CONCLUSIONS: Early in postnatal development, loss of Ostα leads to bile acid accumulation, oxidative stress, and a restitution response in ileum. In addition to its essential role in maintaining bile acid homeostasis, Ostα-Ostß functions to protect the ileal epithelium against bile acid-induced injury. NCBI Gene Expression Omnibus: GSE99579.

14.
Acta Neuropathol Commun ; 4: 4, 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26757882

RESUMO

INTRODUCTION: Glioblastoma with oligodendroglioma component (GBM-O) was recognized as a histologic pattern of glioblastoma (GBM) by the World Health Organization (WHO) in 2007 and is distinguished by the presence of oligodendroglioma-like differentiation. To better understand the genetic underpinnings of this morphologic entity, we performed a genome-wide, integrated copy number, mutational and transcriptomic analysis of eight (seven primary, primary secondary) cases. RESULTS: Three GBM-O samples had IDH1 (p.R132H) mutations; two of these also demonstrated 1p/19q co-deletion and had a proneural transcriptional profile, a molecular signature characteristic of oligodendroglioma. The additional IDH1 mutant tumor lacked 1p/19q co-deletion, harbored a TP53 mutation, and overall, demonstrated features most consistent with IDH mutant (secondary) GBM. Finally, five tumors were IDH wild-type (IDHwt) and had chromosome seven gains, chromosome 10 losses, and homozygous 9p deletions (CDKN2A), alterations typical of IDHwt (primary) GBM. IDHwt GBM-Os also demonstrated EGFR and PDGFRA amplifications, which correlated with classical and proneural expression subtypes, respectively. CONCLUSIONS: Our findings demonstrate that GBM-O is composed of three discrete molecular subgroups with characteristic mutations, copy number alterations and gene expression patterns. Despite displaying areas that morphologically resemble oligodendroglioma, the current results indicate that morphologically defined GBM-O does not correspond to a particular genetic signature, but rather represents a collection of genetically dissimilar entities. Ancillary testing, especially for IDH and 1p/19q, should be used for determining these molecular subtypes.


Assuntos
Neoplasias Encefálicas/genética , Aberrações Cromossômicas , Glioblastoma/complicações , Glioblastoma/genética , Oligodendroglioma/complicações , Oligodendroglioma/genética , Adulto , Idoso , Cromossomos Humanos Par 19/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Expressão Gênica , Genômica/métodos , Humanos , Isocitrato Desidrogenase/genética , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Mutação/genética , Estudos Retrospectivos , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/genética
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