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1.
Medicine (Baltimore) ; 99(1): e18506, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895785

RESUMO

BACKGROUND: Whether the occurrence of refeeding syndrome (RFS), a metabolic condition characterized by electrolyte shifts after initiation of nutritional therapy, has a negative impact on clinical outcomes remains ill-defined. We prospectively investigated a subgroup of patients included in a multicentre, nutritional trial (EFFORT) for the occurrence of RFS. METHODS: In this secondary analysis of a randomized-controlled trial investigating the effects of nutritional support in malnourished medical inpatients, we prospectively screened patients for RFS and classified them as "RFS confirmed" and "RFS not confirmed" based on predefined criteria (i.e. electrolyte shifts, clinical symptoms, clinical context, and patient history). We assessed associations of RFS and mortality within 180 days (primary endpoint) and other secondary endpoints using multivariable regression analysis. RESULTS: Among 967 included patients, RFS was confirmed in 141 (14.6%) patients. Compared to patients with no evidence for RFS, patients with confirmed RFS had significantly increased 180-days mortality rates (42/141 (29.8%) vs 181/826 (21.9%), adjusted odds ratio (OR) 1.53 (95% CI 1.02 to 2.29), P < .05). Patients with RFS also had an increased risk for ICU admission (6/141 (4.3%) vs 13/826 (1.6%), adjusted OR 2.71 (95% CI 1.01 to 7.27), P < .05) and longer mean length of hospital stays (10.5 ±â€Š6.9 vs 9.0 ±â€Š6.6 days, adjusted difference 1.57 days (95% CI 0.38-2.75), P = .01). CONCLUSION: A relevant proportion of medical inpatients with malnutrition develop features of RFS upon hospital admission, which is associated with long-term mortality and other adverse clinical outcomes. Further studies are needed to develop preventive strategies for RFS in this patient population.


Assuntos
Pacientes Internados/estatística & dados numéricos , Desnutrição/mortalidade , Apoio Nutricional/efeitos adversos , Síndrome da Realimentação/mortalidade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Desnutrição/terapia , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Síndrome da Realimentação/etiologia , Fatores de Risco , Taxa de Sobrevida
4.
J Neurosci ; 34(49): 16467-81, 2014 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-25471584

RESUMO

Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic-ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood-brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.


Assuntos
Movimento Celular/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/prevenção & controle , Inflamação/prevenção & controle , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Propilenoglicóis/farmacologia , Esfingosina/análogos & derivados , Animais , Animais Recém-Nascidos , Atrofia/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Corioamnionite/tratamento farmacológico , Corioamnionite/metabolismo , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Cloridrato de Fingolimode , Humanos , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Recém-Nascido , Lipopolissacarídeos , Linfócitos/citologia , NF-kappa B/metabolismo , Gravidez , Propilenoglicóis/uso terapêutico , Ratos , Receptores de Interleucina/metabolismo , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Substância Branca/efeitos dos fármacos
5.
Case Rep Gastrointest Med ; 2014: 790326, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25221678

RESUMO

Enteric duplication cysts are rare congenital malformations that can occur at any point along the digestive tract, most commonly the small bowel. They are characterized by the presence of an outer layer of smooth muscle and an inner lining of mucosa that may resemble any portion of the digestive tract. Less commonly, cases have been reported that also contain mucosal components of nonintestinal origin. This entity is typically diagnosed in young children, but occasionally presents in adolescence and young adulthood. We present a rare case of a 21-year-old male who presented with nonspecific symptoms of abdominal discomfort and weight loss and was later found to have a 9 cm nonenhancing mass in the distal ileum on CT imaging. Laparoscopic dissection of the mass revealed a cystic lesion lined mainly by pseudostratified ciliated columnar respiratory-type epithelium, with patchy areas of squamous epithelium as well as villous columnar epithelium resembling small bowel. The unique histology and advanced patient age make this case a unique presentation of what is already a rare pathological entity.

6.
Stroke ; 44(9): 2623-2627, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23881953

RESUMO

BACKGROUND AND PURPOSE: Plasminogen activator inhibitor-I (PAI-1), a ≈50-kDa serine protease inhibitor, markedly reduces the extravascular toxicity of tissue-type plasminogen activator in experimental hypoxic-ischemic (HI) brain injury of newborns. However, the current treatment with PAI-1 requires intracerebroventricle injection to cross the blood-brain barrier, which is an invasive procedure of limited clinical potential. Thus, we tested whether intranasal administration of PAI-1 can bypass blood-brain barrier and mitigate neonatal HI brain injury. METHODS: Rat pups were subjected to HI, with or without lipopolysaccharide pre-exposure, followed by intranasal delivery of a stable-mutant form of PAI-1 (CPAI). RESULTS: Immunoblotting showed that CPAI sequentially entered the olfactory bulbs and cerebral cortex after intranasal delivery and reduced ≈75% of brain atrophy in HI or lipopolysaccharide-sensitized HI injury. Mechanistically, CPAI attenuated HI-induced plasminogen activators and lipopolysaccharide/HI-induced nuclear factor-κB signaling, neuroinflammation, and blood-brain barrier permeability. CONCLUSIONS: Intranasal delivery of CPAI is an effective treatment of experimental HI brain injury of newborns. Clinical application of this experimental therapy merits further investigation.


Assuntos
Hipóxia-Isquemia Encefálica/tratamento farmacológico , Inibidor 1 de Ativador de Plasminogênio/administração & dosagem , Inativadores de Plasminogênio/administração & dosagem , Inativadores de Plasminogênio/uso terapêutico , Administração Intranasal , Animais , Animais Recém-Nascidos , Atrofia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Modelos Animais de Doenças , Esquema de Medicação , Feminino , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Masculino , Inibidor 1 de Ativador de Plasminogênio/uso terapêutico , Ratos , Ratos Wistar , Inibidores de Serino Proteinase/administração & dosagem , Inibidores de Serino Proteinase/uso terapêutico
7.
Sci Transl Med ; 5(193): 193ra90, 2013 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-23843451

RESUMO

Intracranial hemorrhage in preterm neonates may result in neonatal mortality and functional disabilities, but its pathogenic mechanisms are poorly defined and better therapies are needed. We used a tetracycline-regulated transgenic system to test whether the induction of vascular endothelial growth factor (VEGF) in the germinal matrix leads to intracranial hemorrhage. This genetic strategy initially induced a dense network of loosely adjoined endothelial cells and pericytes near lateral ventricles, similar to the immature vascular rete in human fetal brains. Yet, this rich vascular network transformed into low-vasculature patches correlated with hemorrhage and caspase-3 activation near birth. Gene expression and biochemical analyses suggested that downstream mediators of VEGF in this network include transcriptional factors ETS1 and HIF2α (hypoxia-inducible factor 2α), components of the PDGFß (platelet-derived growth factor ß) and TGFß (transforming growth factor-ß) receptor signaling pathways, matrix metalloproteinase-9 (MMP-9), and cathepsins. Prenatal administration of glucocorticoids markedly reduced mortality and cerebral hemorrhage in mutant animals, as in human neonates. This protective effect was not due to blocking vasculogenesis, but was instead associated with inhibition of neurovascular proteases, notably MMP-9, cathepsin B, and caspase-3. Collectively, these results support a causative role of VEGF in perinatal cerebral hemorrhage and implicate its downstream proteases as potential therapeutic targets.


Assuntos
Hemorragia Cerebral/enzimologia , Hemorragia Cerebral/patologia , Peptídeo Hidrolases/biossíntese , Prosencéfalo/enzimologia , Prosencéfalo/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Animais Recém-Nascidos , Betametasona/farmacologia , Betametasona/uso terapêutico , Caspase 3/metabolismo , Catepsina B/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/genética , Modelos Animais de Doenças , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/patologia , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Perfilação da Expressão Gênica , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Neovascularização Patológica/tratamento farmacológico , Fenótipo , Prosencéfalo/irrigação sanguínea , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Tetraciclina/farmacologia
8.
Exp Neurol ; 247: 447-455, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23353638

RESUMO

Perinatal infection aggravates neonatal hypoxic-ischemic (HI) brain injury and may interfere with therapeutic hypothermia. While the NF-κB signaling pathway has been implicated in microglia activation in infection-sensitized HI, the current therapeutic strategies rely on systemic intervention, which could impair neonatal immunity and increase the risk of severe infection. To devise a brain-targeted anti-NF-κB strategy, we examined the effects of intranasal delivery of tat-NBD peptides in two animal models of neonatal infection-sensitized HI. Kinetic experiments showed that tat-NBD peptides entered the olfactory bulbs rapidly (10-30 min) and peaked in the cerebral cortex around 60 min after intranasal application in P7 rats. Further, intranasal delivery of 1.4 mg/kg tat-NBD, which is only 7% of the intravenous dose in past studies, markedly attenuated NF-κB signaling, microglia activation, and brain damage triggered by HI with 4 or 72 h pre-exposure to the bacterial endotoxin lipopolysaccharide (LPS). In contrast, intranasal delivery of mutant tat-NBD peptides or systemic application of minocycline failed to block LPS-sensitized HI injury. Yet, intranasal delivery of up to 5.6 mg/kg tat-NBD peptides immediately after pure-HI insult showed little protection, likely due to its rapid clearance from the brain and inability to inhibit parenchymal plasminogen activators. Together, these results suggest a novel therapy of infection-sensitized HI brain injury in newborns.


Assuntos
Hipóxia-Isquemia Encefálica/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , NF-kappa B/antagonistas & inibidores , Peptídeos/administração & dosagem , Administração Intranasal , Análise de Variância , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Antígeno CD11b/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Hipóxia-Isquemia Encefálica/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas dos Microfilamentos/metabolismo , Mutação/fisiologia , Ratos , Sais de Tetrazólio
9.
Cereb Cortex ; 23(5): 1218-29, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22556277

RESUMO

Intrauterine infection exacerbates neonatal hypoxic-ischemic (HI) brain injury and impairs the development of cerebral cortex. Here we used low-dose lipopolysaccharide (LPS) pre-exposure followed by unilateral cerebral HI insult in 7-day-old rats to study the pathogenic mechanisms. We found that LPS pre-exposure blocked the HI-induced proteolytic activity of tissue-type plasminogen activator (tPA), but significantly enhanced NF-κB signaling, microglia activation, and the production of pro-inflammatory cytokines in newborn brains. Remarkably, these pathogenic responses were all blocked by intracerebroventricular injection of a stable-mutant form of plasminogen activator protein-1 called CPAI. Similarly, LPS pre-exposure amplified, while CPAI therapy mitigated HI-induced blood-brain-barrier damage and the brain tissue loss with a therapeutic window at 4 h after the LPS/HI insult. The CPAI also blocks microglia activation following a brain injection of LPS, which requires the contribution by tPA, but not the urinary-type plasminogen activator (uPA), as shown by experiments in tPA-null and uPA-null mice. These results implicate the nonproteolytic tPA activity in LPS/HI-induced brain damage and microglia activation. Finally, the CPAI treatment protects near-normal motor and white matter development despite neonatal LPS/HI insult. Together, because CPAI blocks both proteolytic and nonproteolytic tPA neurotoxicity, it is a promising therapeutics of neonatal HI injury either with or without infection.


Assuntos
Lesões Encefálicas/metabolismo , Lesões Encefálicas/prevenção & controle , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/prevenção & controle , Lipopolissacarídeos , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Ativador de Plasminogênio Tecidual/metabolismo , Animais , Animais Recém-Nascidos , Encefalite/induzido quimicamente , Encefalite/metabolismo , Encefalite/prevenção & controle , Hipóxia-Isquemia Encefálica/induzido quimicamente , Camundongos , Ratos
10.
J Interferon Cytokine Res ; 32(8): 368-77, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22509977

RESUMO

The nuclear factor-kappa B (NFκB) signal transduction pathway plays an important role in immunity, inflammation, cell growth, and survival. Since dysregulation of this pathway results in high, constitutive NFκB activation in various cancers and immune disorders, the development of specific drugs to target this pathway has become a focus for treating these diseases. NFκB regulates various aspects of the cellular response to interferon (IFN). However, the role of the upstream regulator of the NFκB signaling pathway, the inhibitor of κB kinase (IKK) complex, on IFN function has not been examined. In the present study, we examined the effects of 2 IKK inhibitors, N-(1,8-Dimethylimidazo[1,2-a]quinoxalin-4-yl)-1,2-ethanediamine hydrochloride (BMS-345541) and 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), on IFN action in several human glioma cell lines. IKK inhibitors inhibit glioma cell proliferation, as well as TNF-induced RelA (p65) nuclear translocation and NFκB-dependent IL8 gene expression. Importantly, BMS-345541 and TPCA-1 differentially inhibit IFN-induced gene expression, completely suppressing MX1 and GBP1 gene expression, while having only a minor effect on ISG15 expression. Furthermore, these IKK inhibitors displayed marked differences in blocking IFN-induced antiviral action against cytopathic effects and replication of vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV). Our results show that the IKK complex plays an important function in IFN-induced gene expression and antiviral activity. Since VSV and EMCV are oncolytic viruses used in cancer therapy, our results indicate the potential synergy in combining IKK inhibitors with oncolytic viruses.


Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Glioma/metabolismo , Quinase I-kappa B/antagonistas & inibidores , Imidazóis/farmacologia , Interferon Tipo I/farmacologia , Quinoxalinas/farmacologia , Tiofenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Efeito Citopatogênico Viral/efeitos dos fármacos , Vírus da Encefalomiocardite/efeitos dos fármacos , Vírus da Encefalomiocardite/fisiologia , Ativação Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/virologia , Humanos , Quinase I-kappa B/metabolismo , Interferon Tipo I/imunologia , Interleucina-8/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Vírus da Estomatite Vesicular Indiana/fisiologia
11.
Cancer Epidemiol ; 36(1): e33-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22056752

RESUMO

Exposure to tobacco carcinogens is the major cause of human lung cancer, but even heavy smokers have only about a 10% life-time risk of developing lung cancer. Currently used screening processes, based largely on age and exposure status, have proven to be of limited clinical utility in predicting cancer risk. More precise methods of assessing an individual's risk of developing lung cancer are needed. Because of their sensitivity to DNA damage, microsatellites are potentially useful for the assessment of somatic mutational load in normal cells. We assessed mutational load using hypermutable microsatellites in buccal cells obtained from lung carcinoma cases and controls to test if such a measure could be used to estimate lung cancer risk. There was no significant association between smoking status and mutation frequency with any of the markers tested. No significant association between case status and mutation frequency was observed. Age was significantly related to mutation frequency in the microsatellite marker D7S1482. These observations indicate that somatic mutational load, as measured using mutation frequency of microsatellites in buccal cells, increases with increasing age but that subjects who develop lung cancer have a similar mutational load as those who remain cancer free. This finding suggests that mutation frequency of microsatellite mutations in buccal cells may not be a promising biomarker for lung cancer risk.


Assuntos
Neoplasias Pulmonares/genética , Repetições de Microssatélites , Mucosa Bucal/patologia , Mutação , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Fumar/efeitos adversos , Fumar/genética
12.
Proc Natl Acad Sci U S A ; 108(18): 7607-12, 2011 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-21502507

RESUMO

The organization of neural progenitors in the developing mammalian neuroepithelium is marked by cadherin-based adherens junctions. Whereas RhoA, a founding member of the small Rho GTPase family, has been shown to play important roles in epithelial adherens junctions, its physiological roles in neural development remain uncertain due to the lack of specific loss-of-function studies. Here, we show that RhoA protein accumulates at adherens junctions in the developing mouse brain and colocalizes to the cadherin-catenin complex. Conditional deletion of RhoA in midbrain and forebrain neural progenitors using Wnt1-Cre and Foxg1-Cre mice, respectively, disrupts apical adherens junctions and causes massive dysplasia of the brain. Furthermore, RhoA-deficient neural progenitor cells exhibit accelerated proliferation, reduction of cell- cycle exit, and increased expression of downstream target genes of the hedgehog pathway. Consequently, both lines of conditional RhoA-deficient embryos exhibit expansion of neural progenitor cells and exencephaly-like protrusions. These results demonstrate a critical role of RhoA in the maintenance of apical adherens junctions and the regulation of neural progenitor proliferation in the developing mammalian brain.


Assuntos
Junções Aderentes/metabolismo , Encéfalo/embriologia , Proliferação de Células , Células-Tronco Neurais/metabolismo , Proteína rhoA de Ligação ao GTP/deficiência , Animais , Bromodesoxiuridina , Imuno-Histoquímica , Imunoprecipitação , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Indóis , Camundongos , Camundongos Mutantes , Microscopia Confocal , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína rhoA de Ligação ao GTP/metabolismo
13.
J Antimicrob Chemother ; 66(4): 702-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21393163

RESUMO

OBJECTIVES: HIV-1 reverse transcriptase (RT) mutations associated with antiviral drug resistance have been extensively characterized in the enzyme polymerase domain. Recent studies, however, have verified the involvement of the RT C-terminal domains (connection and RNase H) in drug resistance to RT inhibitors. In this work, we have characterized the correlation of recently described C-terminal domain mutations with thymidine analogue mutations (TAMs), as well as their phenotypic impact on susceptibility to zidovudine and nevirapine. METHODS: HIV-1 RT sequences from Brazilian patients and from public sequence databases for which the C-terminal RT domains and treatment status were also available were retrieved and analysed for the association of C-terminal mutations and the presence of TAMs and treatment status. Several C-terminal RT mutations previously characterized were introduced by site-directed mutagenesis into an HIV-1 subtype B molecular clone in a wild-type, TAM-1 or TAM-2 pathway context. Mutants were tested for drug susceptibility to the prototypic drugs zidovudine and nevirapine. RESULTS: Subtype B-infected patient database analysis showed that mutations N348I, A360V/T, T377M and D488E were found to be selected independently of TAMs, whereas mutations R358K, G359S, A371V, A400T, K451R and K512R increased in frequency with the number of TAMs in a dose-dependent fashion. Phenotypic analysis of C-terminal mutations showed that N348I, T369V and A371V conferred reduced susceptibility to zidovudine in the context of the TAM-1 and/or TAM-2 pathway, and also conferred dual resistance to nevirapine. Other mutations, such as D488E and Q547K, showed TAM-specific enhancement of resistance to zidovudine. Finally, mutation G359S displayed a zidovudine hypersusceptibility phenotype, both per se and when combined with A371V. CONCLUSIONS: This study demonstrates that distinct RT C-terminal mutations can act as primary or secondary drug resistance mutations, and are associated in a complex array of phenotypes with RT polymerase domain mutations.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , Timidina/análogos & derivados , Substituição de Aminoácidos , Brasil , Infecções por HIV/virologia , HIV-1/enzimologia , HIV-1/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana , Mutagênese Sítio-Dirigida , Proteínas Mutantes/genética , Mutação de Sentido Incorreto , Nevirapina/farmacologia , Estrutura Terciária de Proteína/genética , Timidina/farmacologia , Zidovudina/farmacologia
14.
Laryngoscope ; 119(8): 1531-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19489068

RESUMO

OBJECTIVES/HYPOTHESIS: To examine the role of HPV status in the etiology, prognosis, and treatment of head and neck squamous cell carcinoma in early larynx malignancies. STUDY DESIGN: Retrospective. METHODS: Thirty-eight cases of T1 or carcinoma in situ (CIS) laryngeal lesions were examined for the presence of human papilloma virus (HPV) using an inclusive polymerase chain reaction (PCR)/hybridization technique capable of identifying 37 HPV subtypes. RESULTS: HPV DNA was detected in 6 (16%) of the 38 lesions, representing HPV types 16, 26, 31, 39, and 52, and p16 tumor suppressor protein expression was confirmed in 10 representative cases. This HPV prevalence is higher than that noted in many previous laryngeal cancer studies, possibly due to the relatively large panel of subtypes screened for in this study. Identification of HPV-26, which has been associated with uterine cervical cancer, in an early laryngeal cancer specimen represents the first evidence of this subtype in a laryngeal carcinoma. Consistent with reports focusing on head and neck squamous cell carcinoma (HNSCC) arising from other subsites within the upper aerodigestive tract, patients with HPV-positive laryngeal carcinomas were of younger age and were somewhat less likely to have a history of tobacco use, although the latter of the two findings did not reach statistical significance. CONCLUSIONS: Our findings emphasize the presence of a broad spectrum of HPV types in a relevant proportion of early laryngeal cancers, and together with evidence of an association of HPV tumor status with a more favorable clinical course, provide a rationale for the routine HPV testing of small larynx lesions.


Assuntos
Carcinoma in Situ/patologia , Carcinoma in Situ/virologia , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/virologia , Infecções por Papillomavirus/diagnóstico , Infecções Tumorais por Vírus/diagnóstico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Carcinoma in Situ/etiologia , Carcinoma in Situ/cirurgia , Estudos de Casos e Controles , DNA Viral/análise , Detecção Precoce de Câncer , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Laríngeas/etiologia , Neoplasias Laríngeas/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Reação em Cadeia da Polimerase , Probabilidade , Prognóstico , Valores de Referência , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Estatísticas não Paramétricas , Infecções Tumorais por Vírus/complicações
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