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1.
Front Immunol ; 15: 1373537, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812520

RESUMO

Sex-based differences in immune cell composition and function can contribute to distinct adaptive immune responses. Prior work has quantified these differences in peripheral blood, but little is known about sex differences within human lymphoid tissues. Here, we characterized the composition and phenotypes of adaptive immune cells from male and female ex vivo tonsils and evaluated their responses to influenza antigens using an immune organoid approach. In a pediatric cohort, female tonsils had more memory B cells compared to male tonsils direct ex vivo and after stimulation with live-attenuated but not inactivated vaccine, produced higher influenza-specific antibody responses. Sex biases were also observed in adult tonsils but were different from those measured in children. Analysis of peripheral blood immune cells from in vivo vaccinated adults also showed higher frequencies of tissue homing CD4 T cells in female participants. Together, our data demonstrate that distinct memory B and T cell profiles are present in male vs. female lymphoid tissues and peripheral blood respectively and suggest that these differences may in part explain sex biases in response to vaccines and viruses.


Assuntos
Tonsila Palatina , Humanos , Feminino , Masculino , Criança , Tonsila Palatina/imunologia , Adulto , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Caracteres Sexuais , Pré-Escolar , Adolescente , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Células B de Memória/imunologia , Especificidade de Órgãos/imunologia , Adulto Jovem , Fatores Sexuais , Linfócitos T CD4-Positivos/imunologia , Linfócitos B/imunologia , Memória Imunológica
2.
Am J Otolaryngol ; 45(4): 104361, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729015

RESUMO

OBJECTIVES: This study aims to analyze utilization and reimbursement trends in lingual and hyoid surgery for obstructive sleep apnea (OSA). METHODS: Annual retrospective data on lingual and hyoid OSA surgeries was obtained from the 2000-2021 Medicare Part B National Summary Datafiles. Current Procedural Terminology (CPT) codes utilized included 21,685 (hyoid myotomy and suspension [HMS]), 41,512 (tongue base suspension [TBS]), 41,530 (radiofrequency ablation of the tongue [RFT]) and 42,870 (lingual tonsillectomy [LT]). RESULTS: The number of lingual and hyoid OSA surgeries rose 2777 % from 121 in 2000 to 3481 in 2015, before falling 82.9 % to 594 in 2021. Accordingly, Medicare payments rose 17,899 % from an inflation-adjusted $46,958 in 2000 to $8.45 million in 2015, before falling drastically to $341,011 in 2021. As the number of HMSs (2000: 91; 2015: 84; 2021: 165), TBS (2009: 48; 2015: 31; 2021: 16), and LTs (2000: 121; 2015: 261; 2021: 234) only experienced modest changes in utilization, this change was largely driven by RFT (2009: 340; 2015: 3105; 2021: 179). Average Medicare payments for RFT rose from $1110 in 2009 to $2994 in 2015, before falling drastically to $737 in 2021. CONCLUSION: Lingual and hyoid surgery for OSA has overall fallen in utilization among the Medicare population from 2000 to 2021. However, there was a brief spike in usage, peaking in 2015, driven by the adoption (and then quick dismissal) of RFT. The rise and fall in RFT use coincide with the rise and fall in reimbursement.


Assuntos
Osso Hioide , Apneia Obstrutiva do Sono , Língua , Apneia Obstrutiva do Sono/cirurgia , Apneia Obstrutiva do Sono/economia , Humanos , Estados Unidos , Estudos Retrospectivos , Osso Hioide/cirurgia , Língua/cirurgia , Medicare/economia , Reembolso de Seguro de Saúde/tendências , Reembolso de Seguro de Saúde/economia
3.
J Urol ; 211(1): 46, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37947278
4.
Immunity ; 56(8): 1910-1926.e7, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37478854

RESUMO

Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the cellular dynamics underlying responses to different antigen formats. Here, we sought to understand how antigen-specific B and T cells were activated and participated in adaptive immune responses within the mucosal site. Using a human tonsil organoid model, we tracked the differentiation and kinetics of the adaptive immune response to influenza vaccine and virus modalities. Each antigen format elicited distinct B and T cell responses, including differences in their magnitude, diversity, phenotype, function, and breadth. These differences culminated in substantial changes in the corresponding antibody response. A major source of antigen format-related variability was the ability to recruit naive vs. memory B and T cells to the response. These findings have important implications for vaccine design and the generation of protective immune responses in the upper respiratory tract.


Assuntos
Vacinas contra Influenza , Influenza Humana , Humanos , Formação de Anticorpos , Anticorpos Antivirais , Linfócitos T , Antígenos , Organoides
5.
Otolaryngol Head Neck Surg ; 162(3): 400-407, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31959054

RESUMO

OBJECTIVE: Hypoglossal nerve stimulation (HGNS) is an effective treatment for patients with obstructive sleep apnea (OSA) who fail continuous positive airway pressure (CPAP). We assessed the relationship between patient characteristics and response to HGNS. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary care institution. SUBJECTS AND METHODS: This study included CPAP-intolerant patients with moderate to severe OSA after HGNS system implantation from November 2015 to December 2017. Patient measures, drug-induced sleep endoscopy (DISE) findings, and apnea-hypopnea indices (AHIs) were recorded. RESULTS: Forty-eight patients underwent implantation with the following median measures: age, 66 years; body mass index, 28.6; and neck circumference, 41.0 cm. Patients were classified by Friedman tongue position (II, 27%; III, 56%; IV, 17%) and Mallampati grade (I, 25%; II, 50%; III, 23%; IV, 2%). By DISE, 71% had anterior-posterior palatal collapse. Additionally, 38% had lateral oropharynx collapse; 50%, tongue base collapse; and 27%, epiglottis collapse. Following implantation, median AHI improved from 38.5 to 2.7 (P < .001), and 92% of patients had no worse than mild OSA (8% moderate). Patients with Friedman tongue position grade II/III experienced greater change in AHI as compared with grade IV (94.2% vs 73.8%, P < .001). Patients with Mallampati score I/II experienced greater improvement versus score III/IV (94.7% vs 66.5%, P < .001). No DISE findings, including any obstruction or collapse, were associated with change in AHI. CONCLUSION: This study further confirms HGNS as an effective treatment of CPAP-intolerant OSA. Office measures such as Friedman tongue position IV and Mallampati III/IV were associated with mildly decreased response. DISE findings were not associated with patient response.


Assuntos
Terapia por Estimulação Elétrica , Nervo Hipoglosso , Apneia Obstrutiva do Sono/terapia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Estudos Retrospectivos , Apneia Obstrutiva do Sono/fisiopatologia , Língua/inervação
6.
Otolaryngol Head Neck Surg ; 159(4): 705-711, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30016197

RESUMO

Objective Unexplained chronic cough (UCC) is a perplexing condition treated with neuromodulators. Although previous literature describes the effectiveness of neuromodulators, there is little on the development of tachyphylaxis or dependence to neuromodulators over time. Our objective is to capture the experience of a large cohort of patients with UCC over an extended period, looking for these 2 phenomena. Study Design Case series with chart review. Setting Tertiary care hospital. Subjects and Methods We performed a retrospective review of patients diagnosed with UCC from 2010 to 2014. Patient outcomes were measured through percentage improvement scores. Treatment failures were attributed to no benefit, intolerable side effects, or tachyphylaxis. Tachyphylaxis was defined as the need for higher doses of medication following diminishing therapeutic benefit, while dependence was defined as a failure to stop therapy following attempted de-escalation or resurgence following drug cessation. Results Sixty-eight patients were included in the study. Tachyphylaxis was observed among 35% of patients while dependence was observed among 27% of successfully treated patients, together effecting >50% of the cohort. Sixty-eight percent of patients ultimately experienced successful treatment with neuromodulators, demonstrating strikingly distinct responses to different neuromodulator drug classes. Conclusion Tachyphylaxis and dependence occur frequently during UCC treatment and have a major impact on treatment outcomes. Patients sometimes demonstrate distinct responses to different neuromodulator classes. The majority of patients will experience successful treatment for their cough, although several trials may be required.


Assuntos
Antitussígenos/administração & dosagem , Antitussígenos/efeitos adversos , Tosse/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Taquifilaxia , Adulto , Fatores Etários , Idoso , Doença Crônica , Estudos de Coortes , Tosse/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Falha de Tratamento , Adulto Jovem
7.
Otolaryngol Head Neck Surg ; 159(3): 508-515, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29634404

RESUMO

Objective To evaluate the short- and long-term effects of tricyclic antidepressants (TCAs) and gabapentin in the treatment of unexplained chronic cough (UCC). Study Design Prospective cohort. Setting Tertiary care hospital. Subjects and Methods Patients seen between July 2016 and March 2017 were included following a formal workup and clinical evaluation indicative of UCC. Patients were placed on either a TCA (amitriptyline or nortriptyline) or gabapentin. Leicester Cough Questionnaire (LCQ) and percentage improvement scores were obtained prior to treatment initiation and at 2 and 6 months of neuromodulator treatment. A linear mixed model assessed the change in LCQ score between the 2 treatment time points and baseline scores. Results Twenty-eight patients completed a total of 37 neuromodulator trials. Gabapentin demonstrated statistically significant improvement in LCQ scores at 2 months (2.48 points, P≤ .01) and 6 months (5.40 points, P = .01) of treatment as compared with baseline. Patients taking TCAs demonstrated statistically significant improvement of LCQ scores at 2 months of treatment (3.46 points, P≤ .01). However, the majority of patients discontinued treatment, most commonly secondary to the development of tachyphylaxis after 2 months, precluding analysis at 6 months. Conclusion While both neuromodulator classes demonstrated short-term benefit, the majority of patients discontinue treatment prior to 6 months, with patients taking TCAs discontinuing more frequently than patients on gabapentin. Future investigations are warranted evaluating tachyphylaxis and the utility of dual treatment therapies designed to address peripheral and central sensory pathways involved in UCC.


Assuntos
Amitriptilina/administração & dosagem , Tosse/diagnóstico , Tosse/tratamento farmacológico , Gabapentina/administração & dosagem , Neurotransmissores/uso terapêutico , Nortriptilina/administração & dosagem , Inquéritos e Questionários , Adulto , Idoso , Doença Crônica , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Centros de Atenção Terciária , Fatores de Tempo , Resultado do Tratamento
8.
Am J Otolaryngol ; 39(3): 266-270, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29540289

RESUMO

OBJECTIVES: Hypoglossal nerve stimulation (HNS) therapy is an emerging surgical treatment for select patients with obstructive sleep apnea (OSA). This study aims to compare outcomes in patients with moderate to severe OSA who underwent HNS surgery (Inspire Medical Systems) and those who underwent traditional airway reconstructive surgery, specifically uvulopalatopharyngoplasty (UPPP). METHODS: Patients who underwent HNS implantation (n = 20), all with moderate to severe OSA, inability to adhere to positive pressure therapy, and compliant with previously published inclusion criteria, were compared to a historical cohort that were intolerant of CPAP with similar inclusion criteria who all underwent UPPP (n = 20) with some also undergoing additional procedures such as septoplasty/turbinate reduction. Data including body mass index (BMI), pre- and post-implant apnea-hypopnea index (AHI) were assessed. RESULTS: For patients who underwent HNS, mean preoperative BMI was 28.0. Mean AHI decreased significantly from 38.9 ±â€¯12.5 to 4.5 ±â€¯4.8. All patients achieved an AHI < 20 post implant with 65% (13/20) with an AHI ≤ 5. For patients who underwent traditional airway surgery, mean preoperative BMI was 27.5; mean AHI decreased from 40.3 ±â€¯12.4 to 28.8 ±â€¯25.4. CONCLUSION: While both traditional surgery and HNS are effective treatments for patients with moderate to severe OSA with CPAP intolerance, our study demonstrates that HNS is "curative" in normalizing the AHI to <5 in the majority of patients. For select patients, HNS therapy provides excellent objective improvement in outcome measures.


Assuntos
Terapia por Estimulação Elétrica/métodos , Nervo Hipoglosso , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Apneia Obstrutiva do Sono/terapia , Adulto , Idoso , Índice de Massa Corporal , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Palato/cirurgia , Polissonografia/métodos , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Apneia Obstrutiva do Sono/diagnóstico , Resultado do Tratamento , Úvula/cirurgia
9.
Am J Otolaryngol ; 39(2): 122-126, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29277289

RESUMO

OBJECTIVE: Hypoglossal nerve stimulation is an effective treatment for a subset of patients with Obstructive Sleep Apnea (OSA). Although multiple clinical trials demonstrate its efficacy, no previous literature explores the potential impact the stimulator has on swallowing and voice. Our primary objective is to evaluate patient reported post-operative changes in voice or swallowing following hypoglossal nerve stimulator placement. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary care hospital. SUBJECT AND METHODS: Patients scheduled to receive a hypoglossal stimulator were enrolled. Participants completed baseline Voice Handicap Index-10 (VHI-10) and Eating Assessment Tool-10 (EAT-10) questionnaires preoperatively and again at 1week, 3months, and 6months post-operatively following placement of a hypoglossal nerve stimulator. RESULTS: 9 males and 5 females completed the study. The mean pre-operative VHI-10 and EAT-10 score was 3 and 0.8 respectively. Using linear mixed models, a clinically and statistically significant increase in the mean EAT-10 score was observed post-operatively at 1week (p=0.007), which was not observed at the time points the stimulator was active. A clinically and statistically significant decrease in VHI-10 score was observed following 2months of active stimulator use (p=0.02), which was not observed at any other time point. CONCLUSION: The implantation and use of the hypoglossal nerve stimulator over 5months did not demonstrate any sustained, patient reported changes in voice handicap and swallowing function. While larger studies are warranted, our findings can be used to provide further informed consent for hypoglossal nerve stimulator implantation.


Assuntos
Deglutição/fisiologia , Terapia por Estimulação Elétrica/métodos , Nervo Hipoglosso/fisiopatologia , Apneia Obstrutiva do Sono/cirurgia , Voz/fisiologia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Apneia Obstrutiva do Sono/fisiopatologia , Inquéritos e Questionários , Resultado do Tratamento
10.
Ann Otol Rhinol Laryngol ; 125(10): 785-800, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27357971

RESUMO

OBJECTIVES: Celecoxib is a cyclooxygenase-2-specific inhibitor indicated to treat acute pain and pain secondary to osteoarthritis and rheumatoid arthritis. Surgical models of acute pain have demonstrated superior pain relief to placebo. The objective of this study was to test the safety and efficacy of celecoxib for pain relief after tonsillectomy compared to placebo. METHODS: Adult subjects were randomized to 200 mg celecoxib versus placebo with a loading dose the night before surgery then twice daily for 10 days. Subjects were instructed to supplement the study drug with hydrocodone/acetaminophen liquid or acetaminophen for pain as needed. Subjects completed a daily diary regarding their pain, nausea, vomiting, diet, and activity. RESULTS: Seventeen subjects enrolled. Intraoperative blood loss was similar between groups, and no subject had postoperative bleeding. Three patients returned to the emergency department for treatment, and 2 patients could not complete the diaries, all in the placebo group. Subjects in the placebo group required statistically significant (P < .05) higher doses of narcotic and acetaminophen to control pain. Pain and diet rating scores were slightly better in the celecoxib group compared to placebo. CONCLUSIONS: In this small cohort, celecoxib reduced postoperative narcotic and acetaminophen requirements compared to placebo without complications.


Assuntos
Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Tonsilectomia , Tonsilite/cirurgia , Acetaminofen/uso terapêutico , Adulto , Analgésicos não Narcóticos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Doença Crônica , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Hidrocodona/uso terapêutico , Masculino , Manejo da Dor , Medição da Dor , Estudos Prospectivos , Recidiva , Adulto Jovem
11.
Otolaryngol Head Neck Surg ; 154(5): 957-62, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26932952

RESUMO

OBJECTIVE: Understand real-world prescription patterns for patients presenting with a first diagnosis of ARS and evaluate adherence to published medical guidelines. STUDY DESIGN: Retrospective administrative database analysis. SETTING: US-based outpatient settings. METHODS: From a US claims database (MarketScan), 99,033 patients were identified with acute rhinosinusitis (ARS) in 2012 ("index"), with a complete medical and prescription history for 12 months preindex and 18 months postindex and no diagnoses of asthma or chronic rhinosinusitis. Of these, a random 10,000-patient sample was generated matched for age and sex to the initial cohort. Prescriptions and procedures at index, as well as complications up to 12 months postindex, were analyzed. RESULTS: Nearly 90% of all patients received a prescription at index. Antibiotics were prescribed for 84.8% patients, followed by antitussives (16.2% for adults, 6.2% for pediatrics), nasal corticosteroids (15.5% adults, 7.5% for pediatrics), and systemic corticosteroids (10.3% for adults, 5.5% for pediatrics), with 49% adults and 29% children receiving >1 medication at first visit. Macrolides were the most frequently prescribed antibiotics (35.6% adults, 28.6% pediatrics), followed by amoxicillin/clavulanate and amoxicillin. Within 12 months of index, 3 patients presented with meningitis and 3 with orbital cellulitis. CONCLUSION: Significant variability in ARS treatment was observed, highlighting the need for heightened awareness of existing guidelines.


Assuntos
Padrões de Prática Médica/estatística & dados numéricos , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Doença Aguda , Feminino , Fidelidade a Diretrizes , Humanos , Masculino , Estudos Retrospectivos , Estados Unidos
12.
Transl Oncol ; 1(4): 202-8, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19043531

RESUMO

The presence of cervical lymph node metastases in head and neck squamous cell carcinoma (HNSCC) is the strongest determinant of patient prognosis. Owing to the impact of nodal metastases on patient survival, a system for sensitive and accurate detection is required. Clinical staging of lymph nodes is far less accurate than pathological staging. Pathological staging also suffers limitations because it fails to detect micrometastasis in a subset of nodal specimens. To improve the sensitivity of existing means of diagnosing metastatic disease, many advocate the use of molecular markers specific for HNSCC cells. MicroRNA (miRNA) are short noncoding segments of RNA that posttranscriptionally regulate gene expression. Approximately one third of all miRNA will exhibit substantial tissue specificity. Using a quantitative reverse transcription-polymerase chain reaction-based assay, we examined the expression of microRNA-205 (mir-205) across tissues and demonstrated that its expression is highly specific for squamous epithelium. We applied this assay to tissue samples, and we could detect metastatic HNSCC in each positive lymph node specimen, whereas benign specimens did not express this marker. When compared to metastases from other primary tumors, HNSCC-positive lymph nodes were distinguishable by the high expression of this marker. Using an in vitro lymphoid tissue model, we were able to detect as little as one squamous cell in a background of 1 million lymphocytes. By combining the sensitivity of quantitative reverse transcription-polymerase chain reaction with the specificity of mir-205 for squamous epithelium, we demonstrate a novel molecular marker for the detection of metastatic HNSCC.

13.
Ann Otol Rhinol Laryngol ; 117(7): 506-9, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18700425

RESUMO

OBJECTIVES: Lingual tonsillar hypertrophy is an underappreciated cause of dysphagia and is believed to impede swallowing function by inhibition of laryngeal elevation and epiglottic inversion due to mechanical interference by bulky tongue base tissue. We present a case of severe dysphagia secondary to idiopathic tongue base hypertrophy that was treated with coblation lingual tonsillectomy and tongue base reduction. METHODS: We report a case and discuss the relevant literature regarding tongue base hypertrophy and surgical interventions to treat the enlarged base of the tongue. RESULTS: Symptoms of dysphagia and globus sensation and signs of decreased epiglottic inversion and laryngeal penetration improved markedly after surgical reduction of hypertrophied lingual tonsillar tissue using coblation. Preoperative and postoperative clinical imaging and radiographs are presented to show the reduction of tongue base size, correlated with the patient's improved clinical function. CONCLUSIONS: Coblation-assisted lingual tonsillectomy and tongue base reduction can successfully treat dysphagia secondary to tongue base hypertrophy.


Assuntos
Ablação por Cateter , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/cirurgia , Língua/patologia , Tonsilectomia/métodos , Adulto , Feminino , Humanos , Hipertrofia , Tonsila Palatina/patologia
14.
Arch Otolaryngol Head Neck Surg ; 134(4): 355-62, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18427000

RESUMO

OBJECTIVE: To determine how vascular endothelial growth factor C (VEGF-C) affects tumor cell invasion and motility in squamous cell carcinoma of the head and neck (SCCHN). DESIGN: A molecular biology study. The VEGF-C coding sequence was cloned into an expression vector and stably transfected into the SCCHN cell line SCC116 to create the SCC116-VEGFC line. RNA interference (RNAi) was used to block VEGF-C expression. An adenoviral system for expressing VEGF-C RNAi was developed and tested. SETTING: An academic hospital laboratory. MAIN OUTCOME MEASURES: Relative VEGF-C RNA levels were determined by real-time quantitative reverse transcriptase-polymerase chain reaction, and protein expression was evaluated by Western blot. Cellular invasion was evaluated by 24-hour semipermeable membrane transit assay. RESULTS: SCC116-VEGFC cells had markedly increased expression of VEGF-C protein and RNA compared with normal SCC116 controls. SCC116-VEGFC cells produced marked increases in cellular invasion and motility compared with SCC116 cells. Blockade of VEGF-C expression by transfection of a VEGF-C RNAi expression plasmid into both SCC116 and SCC116-VEGFC cells induced a 38% decrease in SCCHN invasion and motility as tested by a semipermeable membrane invasion assay. We developed an adenoviral expression system for VEGF-C RNAi, which also induced a dose-dependent decrease in cellular invasion in the highly invasive DM12 cell line. CONCLUSIONS: These studies demonstrate that intracellular VEGF-C levels modulate in vitro SCCHN motility and invasion. Further work is needed to clarify the specific receptors and signaling pathways that are involved in SCCHN motility. Molecular therapies that inhibit the VEGF-C pathway may have clinical potential in the treatment of lymphatic metastasis in SCCHN.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Interferência de RNA , Fator C de Crescimento do Endotélio Vascular/fisiologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Movimento Celular , Humanos , Invasividade Neoplásica , Transdução Genética
16.
Cancer Res ; 67(8): 3801-8, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17440094

RESUMO

Celecoxib inhibits proliferation and induces apoptosis in human tumors, but the molecular mechanisms for these processes are poorly understood. In this study, we evaluated the ability of celecoxib to induce toxicity in head and neck squamous cell carcinomas (HNSCC) and explored the relationships between celecoxib-induced cell cycle inhibition and toxicity in HNSCC. Celecoxib inhibited the proliferation of UM-SCC-1 and UM-SCC-17B cells both in vitro and in vivo, accompanied by G(1) phase cell cycle arrest and apoptosis. Celecoxib induced p21(waf1/cip1) at the transcriptional level independent of wild-type p53 function, leading to decreased expression of cyclin D1 and hypophosphorylation of Rb, with subsequent marked downstream decreases in nuclear E2F-1 protein expression and E2F transactivating activity by luciferase reporter assay. Cell cycle phase-specific cytometric sorting showed that celecoxib induced clonogenic toxicity preferentially to cells within the S phase greater than G(1) and G(2) phases. Levels of p21(waf1/cip1) and cyclin D1 protein were reduced in the S phase compared with the G(1) and G(2) phases, suggesting a possible protective role for p21(waf1/cip1) expression in celecoxib toxicity. In conclusion, we show that celecoxib has marked antiproliferative activity against head and neck cancer cells through transcriptional induction of p21(waf1/cip1) and G(1) phase accumulation leading to S phase-specific clonogenic toxicity. We additionally show that a profound inhibition of nuclear E2F function provides a possible mechanism for this S phase-specific toxicity.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Fase G1/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Pirazóis/farmacologia , Fase S/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Celecoxib , Processos de Crescimento Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/genética , Fatores de Transcrição E2F/antagonistas & inibidores , Fatores de Transcrição E2F/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Camundongos , Camundongos Nus , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ativação Transcricional/efeitos dos fármacos
17.
Mol Carcinog ; 46(10): 857-64, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17415779

RESUMO

This study was performed to compare the relative antineoplastic activity of 10 different non-steroidal anti-inflammatory drugs (NSAIDs) in clinical use, and to investigate the underlying mechanisms of this activity in a squamous cell carcinoma of the head and neck model (SCCHN). A standard 5-day MTT assay was used to calculate IC(50) values in UM-SCC-1 cells for 10 NSAIDs, including celecoxib, rofecoxib, sulindac sulfide, sulindac sulfone, indomethacin, ketoprofen, flurbiprofen, naproxen, piroxicam, and aspirin. Celecoxib, a COX-2 specific inhibitor, was by far the most potent NSAID, with an IC(50) of 39.9 +/- 1.1 microM, followed by sulindac sulfide (116.5 +/- 2.34 microM). Celecoxib and sulindac sulfide also induced more activation of caspase-3 than any other NSAID. Cell cycle analysis showed that celecoxib and sulindac sulfide both induced a 3-fold increase in G(1) phase distribution, and this correlated with strong induction of p21(waf1/cip1), inhibition of cyclin D1, and hypophosphorylation of Rb. Celecoxib and sulindac sulfide treatment induced strong downstream inhibition of E2F transactivating activity as determined by a luciferase reporter assay. These data demonstrate the wide range of activity of various NSAID agents, and reveal a mechanism of action through cell cycle inhibition and induction of apoptosis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/farmacologia , Fase G1/efeitos dos fármacos , Apoptose , Celecoxib , Fatores de Transcrição E2F/antagonistas & inibidores , Humanos , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sulindaco/análogos & derivados , Sulindaco/farmacologia , Células Tumorais Cultivadas
18.
Cancer Biol Ther ; 6(1): 30-9, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17172818

RESUMO

Sulindac sulfide and sulindac sulfone have demonstrated anti-neoplastic and chemo-preventive activity against various human tumors, but few studies have examined the relative effectiveness of these drugs against squamous cell carcinoma of the head and neck (SCCHN). These compounds are metabolites of the nonsteroidal anti-inflammatory drug sulindac and differ in their ability to inhibit cyclooxygenase-2 (COX-2) enzyme function. Sulindac sulfide (the sulindac metabolite with COX-2 inhibitory function) demonstrated strong cell growth inhibition as measured by MTT and growth assays in UM-SCC-1 and SCC-25 cells, while sulindac sulfone had only moderate effect. Growth inhibition by sulindac sulfide was associated with a significant increase in percent G cells and activation of caspase-3. Sulindac sulfide induced expression of p21wafl/cipl in a dose-dependent fashion, decreased cyclin D1 protein levels, and increased Rb hypophosphorylation. p21waf1/cip1 protein levels increased without a significant increase in wild-type p53, suggesting that sulindac sulfide induces a p53-independent pathway regulating p2lwafl/ciP1 protein levels in SCCHN. Sulindac sulfide also induced dose-dependent expression of PPAR-gamma. In contrast, sulindac sulfone did not significantly alter apoptosis, cell cycle distribution or G1 checkpoint protein expression at doses below 200 microM. These results demonstrate the differential activity of sulindac metabolites and support the hypothesis that sulindac sulfide induced perturbations in SCCHN cellular proliferation could be regulated both by p21waf1/cip1-dependent cytostatic and caspase-dependent cytotoxic pathways.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Sulindaco/análogos & derivados , Apoptose , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Humanos , PPAR gama/antagonistas & inibidores , Sulindaco/metabolismo , Sulindaco/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima
19.
Laryngoscope ; 115(12): 2262-5, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16369177

RESUMO

The practice of injection laryngoplasty under local anesthesia has become more common as both the indications for the procedure and the number of injectable substances increased. Modifications to the injection techniques used for vocal fold augmentation have been described over the last decade that reflect changes in the established percutaneous and transoral approaches. These percutaneous and transoral injection techniques for the treatment of dysphonia secondary to glottic incompetence are well described and provide an adequate approach for most cases. However, these traditional methods may be difficult to master, require great patient tolerance, and may be impossible to perform when anatomic or physiologic barriers exist. We describe a new application of the fiberoptic transnasal endoscope to perform laryngeal injection using a flexible needle through a port in the endoscope. This technique is easily mastered and readily tolerated by patients who would not be candidates for the other injection techniques under local anesthesia. We present our favorable experience with this technique and identify its shortcomings coupled with recommendations to address future technical modifications.


Assuntos
Colágeno/administração & dosagem , Laringoscopia , Implantação de Prótese/métodos , Prega Vocal/cirurgia , Distúrbios da Voz/cirurgia , Humanos , Injeções , Nariz , Resultado do Tratamento
20.
Ann Otol Rhinol Laryngol ; 114(9): 677-80, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16240929

RESUMO

OBJECTIVES: Oral melanoacanthoma is a rare condition that presents as a pigmented, painful lesion, most commonly on the buccal mucosa. Argon plasma coagulation is a new treatment option for benign oral lesions and is hypothesized to be efficacious for this rare mucosal disorder. METHODS: Treatment of a case and a review of the English-language literature were performed. RESULTS: One patient received a diagnosis of oral melanoacanthoma, and argon plasma coagulation treatment resulted in ablation of the lesion with excellent mucosal healing. A review of the literature demonstrated that this lesion is most commonly associated with black (90.9%), adult female (69.7%) patients and is most commonly located on the buccal mucosa (64.7%). CONCLUSIONS: Oral melanoacanthoma is a rare, benign mucosal lesion that may require surgical intervention for symptomatic relief. Argon plasma coagulation is a relatively safe and effective means of treating this lesion. Argon plasma coagulation treatment may be expanded to include other benign, superficial lesions of the oral mucosa.


Assuntos
Acantoma/cirurgia , Eletrocoagulação/métodos , Melanoma/cirurgia , Neoplasias Bucais/cirurgia , Acantoma/etnologia , Negro ou Afro-Americano , Biópsia por Agulha Fina , Células Dendríticas/patologia , Seguimentos , Humanos , Masculino , Melanócitos/patologia , Melanoma/etnologia , Pessoa de Meia-Idade , Neoplasias Bucais/etnologia , Resultado do Tratamento
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