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1.
Neoplasma ; 67(2): 259-266, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31777263

RESUMO

Nasopharyngeal carcinoma (NPC) is a rare form of the head and neck cancer of the epithelial lining of the nasopharynx and exhibits the highest metastatic rate among head and neck cancers. Underlying mechanisms of metastasis remain largely unknown. Here, we explored whether Notch1 affects the invasion and metastasis of NPC cells. In vitro migration and invasion capacities were evaluated after the knockdown of Notch1 expression in NPC cells. To investigate the role of Notch1 in in vivo metastasis, we examined the metastatic ability to the lungs following administration of cancer cells via mouse tail vein. The expression of epithelial-mesenchymal transition (EMT) markers associated with Notch1-mediated metastasis was investigated, and their roles in metastasis and relationship with Notch1 expression were investigated. Suppression of Notch1 expression increased the ability of NPC cells to invade Matrigel in vitro. Knockdown of Notch1 expression in NPC cells resulted in extensive lung metastasis in a mouse model and increased the mRNA expression of Slug in NPC cells. Slug-specific RNA interference resulted in the loss of the metastatic and invasion capacities in Notch1-suppressed NPC cells. These findings show that Notch1 has a significant suppressive role in the regulation of metastasis in NPCs, suggestive of its prudent use in clinical trials.


Assuntos
Neoplasias Pulmonares/secundário , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Receptor Notch1/genética , Fatores de Transcrição da Família Snail/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Camundongos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Invasividade Neoplásica , Metástase Neoplásica , Interferência de RNA
2.
Anaesthesia ; 71(8): 921-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26993374

RESUMO

The aim of this prospective, blinded, randomised controlled study was to compare novices' acquisition of the technical skills of ultrasound-guided regional anaesthesia using either a meat phantom model or fresh-frozen human cadavers. The primary outcome was the time taken to successfully perform an ultrasound-guided sciatic nerve block on a cadaver; secondary outcomes were the cumulative score of errors, and best image quality of the sciatic nerve achieved. After training, the median (IQR [range]) time taken to perform the block was 311(164-390 [68-600]) s in the meat model trained group and 210 (174-354 [85-600]) s in the fresh-frozen cadaver trained group (p = 0.24). Participants made a median (IQR [range]) of 18 (14-33 [8-55]) and 15 (12-22 [8-44]) errors in the two groups respectively (p = 0.39). The image quality score was also not different, with a median (IQR [range]) of 62.5 (59.4-65.6 [25.0-100.0])% vs 62.5 (62.5-75.0 [25.0-87.5])% respectively (p = 0.58). The training and deliberate feedback improved all participants' block performance, the median (IQR [range]) times being 310 (206-532 [110-600]) s before and 240 (174-354 [85-600]) s after training (p = 0.02). We conclude that novices taught ultrasound scanning and needle guidance skills using an inexpensive and easily constructed meat model perform similarly to those trained on a cadaveric model.


Assuntos
Anestesiologia/educação , Bloqueio Nervoso/métodos , Ultrassonografia de Intervenção/métodos , Cadáver , Competência Clínica , Feminino , Humanos , Masculino , Estudos Prospectivos , Ensino
3.
Anaesthesia ; 70(12): 1401-11, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26558857

RESUMO

The aim of this study was to create and evaluate the validity, reliability and feasibility of the Regional Anaesthesia Procedural Skills tool, designed for the assessment of all peripheral and neuraxial blocks using all nerve localisation techniques. The first phase was construction of a 25-item checklist by five regional anaesthesia experts using a Delphi process. This checklist was combined with a global rating scale to create the tool. In the second phase, initial validation by 10 independent anaesthetists using a test-retest methodology was successful (Cohen kappa ≥ 0.70 for inter-rater agreement, scores between test to retest, paired t-test, p > 0.12). In the third phase, 70 clinical videos of trainees were scored by three blinded international assessors. The RAPS tool exhibited face validity (p < 0.026), construct validity (p < 0.001), feasibility (mean time to score < 3.9 min), and overall reliability (intraclass correlation coefficient 0.80 (95% CI 0.67-0.88)). The Regional Anaesthesia Procedural Skills tool used in this study is a valid and reliable assessment tool to score the performance of trainees for regional anaesthesia.


Assuntos
Anestesiologia/educação , Competência Clínica , Avaliação Educacional , Bloqueio Nervoso/métodos , Lista de Checagem , Humanos
4.
Br J Cancer ; 111(11): 2122-30, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25321191

RESUMO

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) display cellular heterogeneity and contain cancer stem cells (CSCs). Sex-determining region Y [SRY]-box (SOX)2 is an important regulator of embryonic stem cell fate and is aberrantly expressed in several types of human tumours. Nonetheless, the role of SOX2 in HNSCC remains unclear. METHODS: We created cells ectopically expressing SOX2 from previously established HNSCC cells and examined the cell proliferation, self-renewal capacity, and chemoresistance of these cells compared with control cells. In addition, we knocked down SOX2 in primary spheres obtained from HNSCC tumour tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined the clinical relevance of SOX2 expression in HNSCC patients. RESULTS: SOX2 is aberrantly expressed in primary tissue of HNSCC patients but not in healthy tissue. SOX2 expression correlated with tumour recurrence and poor prognosis of HNSCC patients. Ectopic expression of SOX2 induced cell proliferation via cyclin B1 expression and stemness-associated features, such as self-renewal and chemoresistance. In addition, a knockdown of SOX2 in HNSCC CSCs attenuated their self-renewal capacity, chemoresistance (through ABCG2 suppression), invasion capacity (via snail downregulation), and in vivo tumorigenicity. CONCLUSIONS: These results suggest that SOX2 may have important roles in the 'stemness' and progression of HNSCC. Targeting SOX2-positive tumour cells (CSCs) could be a new therapeutic strategy in HNSCCs.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Células-Tronco Neoplásicas/patologia , Fatores de Transcrição SOXB1/fisiologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/fisiologia , Animais , Carcinogênese , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Proliferação de Células , Ciclina B1/fisiologia , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Camundongos , Invasividade Neoplásica , Proteínas de Neoplasias/fisiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço
5.
J Appl Microbiol ; 115(5): 1172-85, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23910250

RESUMO

AIMS: The purpose of this study was to isolate, identify and characterize an antifungal compound from Lactobacillus plantarum KCC-10 from forage silage with potential beneficial properties. METHODS AND RESULTS: The 16S rRNA gene-based phylogenetic affiliation was determined using bioinformatic tools and identified as Lactobacillus sp. KCC-10 with 100% sequence similarity to L. plantarum. The antifungal substances were extracted with ethyl acetate from spent medium in which Lactobacillus sp. KCC-10 was cultivated. Antifungal activity was assessed using the broth microdilution technique. The compounds were obtained by eluting the crude extract with various concentrations of solvents followed by chromatographic purification. Based on the infrared, (13) C nuclear magnetic resonance (NMR) and (1) H NMR spectral data, the compound was identified as a phenolic-related antibiotic. The minimum inhibitory concentration of the compound against Aspergillus clavatus, A. oryzae, Botrytis elliptica and Scytalidium vaccinii was 2.5 mg ml(-1) and that against A. fumigatus, A. niger and S. fusca was 5.0 mg ml(-1) , respectively. In addition, Lactobacillus sp. KCC-10 was highly sensitive towards oxgall (0.3%) but grew well in the presence of sodium taurocholate (0.3%). An antimicrobial susceptibility pattern was an intrinsic feature of this strain; thus, consumption does not represent a health risk to humans or animals. CONCLUSION: Novel L. plantarum KCC-10 with antifungal and potential probiotic properties was characterized for use in animal food. SIGNIFICANCE AND IMPACT OF THE STUDY: This study revealed that L. plantarum KCC-10 exhibited good antifungal activity similar to that of probiotic Lactobacillus strains.


Assuntos
Antifúngicos/química , Lactobacillus plantarum/química , Silagem/microbiologia , Aminas/química , Antifúngicos/isolamento & purificação , Aspergillus/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Lactobacillus plantarum/genética , Lactobacillus plantarum/isolamento & purificação , Lolium/microbiologia , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Fenóis/química , Fenóis/isolamento & purificação , Filogenia , Probióticos , RNA Ribossômico 16S/genética
7.
J Exp Med ; 189(11): 1765-76, 1999 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-10359580

RESUMO

Different T cell subsets exhibit distinct capacities to migrate into peripheral sites of inflammation, and this may in part reflect differential expression of homing receptors and chemokine receptors. Using an adoptive transfer approach, we examined the ability of functionally distinct subsets of T cells to home to a peripheral inflammatory site. The data directly demonstrate the inability of naive T cells and the ability of effector cells to home to inflamed peritoneum. Furthermore, interleukin (IL)-12 directs the differentiation of either CD4(+) or CD8(+) T cells into effector populations that expresses functional E- and P-selectin ligand and that are preferentially recruited into the inflamed peritoneum compared with T cells differentiated in the presence of IL-4. Recruitment can be blocked by anti-E- and -P-selectin antibodies. The presence of antigen in the peritoneum promotes local proliferation of recruited T cells, and significantly amplifies the Th1 polarization of the lymphocytic infiltrate. Preferential recruitment of Th1 cells into the peritoneum is also seen when cytokine response gene 2 (CRG-2)/interferon gamma-inducible protein 10 (IP-10) is used as the sole inflammatory stimulus. We have also found that P-selectin binds only to antigen-specific T cells in draining lymph nodes after immunization, implying that both antigen- and cytokine-mediated signals are required for expression of functional selectin-ligand.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/fisiologia , Selectinas/metabolismo , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Movimento Celular/fisiologia , Quimiocina CXCL10 , Quimiocinas CXC/administração & dosagem , Selectina E/metabolismo , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Interleucina-12/farmacologia , Interleucina-4/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Monocinas/administração & dosagem , Selectina-P/metabolismo , Receptores de Retorno de Linfócitos/fisiologia , Células Th1/imunologia , Células Th1/patologia , Células Th1/fisiologia , Células Th2/imunologia , Células Th2/patologia , Células Th2/fisiologia
8.
Br J Surg ; 96(3): 253-7, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19224514

RESUMO

BACKGROUND: The indications for and appropriate extent of prophylactic central lymph node (CLN) dissection for clinically node-negative patients with unilateral papillary thyroid microcarcinoma (PTMC) are unknown. METHODS: The frequency, patterns and predictive factors for CLN metastases in 86 patients with unilateral PTMC and a clinically node-negative neck were analysed with respect to age and sex; metastasis, age, completeness, invasiveness, size (MACIS) score; tumour size; number and location of tumours; presence of ipsilateral CLN metastases; and presence of lymphovascular or capsular invasion. All patients underwent total thyroidectomy and CLN dissection. RESULTS: Twenty-seven (31 per cent) of 86 patients had metastatic CLNs: 18 ipsilateral and nine bilateral. Univariable analysis suggested male sex and tumour size greater than 0.5 cm to be significant factors in predicting ipsilateral CLN metastases. Only ipsilateral nodal positivity was a significant predictor of contralateral CLN metastases in multivariable analysis (P = 0.007). CONCLUSION: CLN metastases are relatively common in PTMC.


Assuntos
Carcinoma Papilar/cirurgia , Excisão de Linfonodo/métodos , Esvaziamento Cervical/métodos , Complicações Pós-Operatórias/etiologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/métodos , Adulto , Idoso , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
Int J Clin Pharmacol Ther ; 47(12): 770-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19954716

RESUMO

OBJECTIVE: To evaluate the bioequivalence of a gliclazide/metformin combination tablet (at dose of 80/500 mg) with co-administration of metformin (500 mg) and gliclazide (80 mg) as individual tablets in healthy male Korean volunteers. SUBJECTS, MATERIALS AND METHODS: The study was conducted as an open-label, randomized, 2-period crossover design in 32 healthy male Korean volunteers who received a combination tablet of gliclazide/metformin at a dose of 80/500 mg or co-administration of gliclazide and metformin as individual tablets in each study period. There was a 7-day washout period between doses. Serum concentrations of gliclazide and metformin up to 32 hours after administration were determined using a validated HPLC method with UV detection. The pharmacokinetic parameters such as AUC0-t (the area under the curve from zero to the time), AUC0- yen (the area under the curve from zero to infinity), Cmax (maximum serum concentration), tmax (time to reach Cmax) and t1/2 (terminal half-life), were analyzed by non-compartmental analysis. Analysis of variance (ANOVA) was carried out using logarithmically transformed AUC0-t, AUC0- yen and Cmax, and untransformed tmax. In addition, blood glucose concentration was also logarithmically transformed and analyzed. Tolerability and safety profiles were also investigated. RESULTS: There were no significant differences between the single combination tablet and the individual tablets in AUC0-t, AUC0- yen, Cmax and blood glucose concentration. The point estimates (90% confidence intervals) for AUC0-t, AUC0- yen and Cmax were 1.0293 (0.9476 - 1.1178), 1.0253 (0.9185 - 1.1443) and 1.0425 (0.9986 - 1.0883) for gliclazide, and 0.9887 (0.9137 - 1.0697), 0.9915 (0.9189 - 1.0697) and 0.9882 (0.9295 - 1.0505) for metformin, respectively, satisfying the bioequivalence criteria of 80 - 125% as proposed by the US FDA and the Korean legislation. Significant F test values were found between the subjects and subject nested sequence (SEQ) for AUC0-t and Cmax, indicating substantial inter-subject variation in the pharmacokinetics of gliclazide and metformin. However, a SEQ effect in the two-way crossover design did not impair the bioequivalence conclusion. No statistically significant differences were found for tmax and blood glucose concentration between two treatments. CONCLUSION: The combination tablet of gliclazide/metformin is bioequivalent to co-administration of individual tablets. As a result, the combination tablets are regarded therapeutically equivalent and exchangeable to the co-administration of individual tablets in clinical practice. Moreover, the combination tablets are expected to improve convenience and adherence to prescribed therapy and to contribute to better blood glucose control for patients with Type 2 diabetes.


Assuntos
Gliclazida/administração & dosagem , Gliclazida/farmacocinética , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Metformina/administração & dosagem , Metformina/farmacocinética , Adulto , Estudos Cross-Over , Combinação de Medicamentos , Gliclazida/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Coreia (Geográfico) , Masculino , Metformina/efeitos adversos , Comprimidos , Equivalência Terapêutica
10.
Audiol Neurootol ; 13(3): 182-6, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18212518

RESUMO

The aims of the study were to characterize the vibration-induced nystagmus (VIN) in patients with unilateral vestibular neuritis (VN) and Ménière's disease (MD), and to clarify the clinical significance of VIN by comparing it with caloric results in patients with VN and MD. We recorded eye movements from 22 VN patients and 24 MD patients using unilateral 100-Hz vibration on the mastoid bone. Eye movements were analyzed and the maximum value of slow-phase eye velocity was obtained during vibration on each mastoid. The average value of slow-phase velocities was calculated. Spontaneous nystagmus was subtracted from the slow-phase velocity, whenever it was present. A canal paresis (CP) greater than 25% was considered pathologic. All but one VN patient showed pathologic CP with the direction of the slow-phase eye movement of VIN toward the lesioned side. Fifteen (63%) out of 24 MD patients showed VIN with the slow-phase eye movement directed to the lesioned side. Pathologic CP was present in 9 (38%) out of 24 MD patients and 8 of them showed slow-phase eye movements of VIN directed to the lesioned side. There were also 8 other MD patients who showed slow-phase eye movement of VIN directed to the intact side. Among them, 3 patients with the slow-phase eye movement more than 5 degrees /s showed CP on the intact side. The amplitude of slow-phase eye velocity showed a significant correlation with CP in patients with either VN or MD. There was no significant difference in the slope of the regression lines between the VN and MD groups. Our results suggest that VIN may probe imbalance of canal responses to low-frequency stimulation similar to the caloric test. It also shows that VIN can help in detecting vestibular imbalance using a stimulation mechanism different from the caloric test. The VIN test can be helpful in determining the lesioned side in patients with VN; however, it has some limitations in localizing the lesioned side in patients with MD.


Assuntos
Processo Mastoide/fisiologia , Nistagmo Patológico/etiologia , Neuronite Vestibular/fisiopatologia , Vibração , Estimulação Acústica , Adulto , Idoso , Meato Acústico Externo/fisiologia , Meato Acústico Externo/fisiopatologia , Movimentos Oculares , Feminino , Lateralidade Funcional/fisiologia , Humanos , Masculino , Processo Mastoide/fisiopatologia , Pessoa de Meia-Idade , Nistagmo Patológico/fisiopatologia , Valores de Referência
11.
Int J Oral Maxillofac Surg ; 37(5): 494-6, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18276113

RESUMO

The incidence of collision tumor is exceedingly rare. There are only four published case reports. This is the first report of a case of collision metastasis of squamous cell carcinoma (SCC) of the oral tongue and incidental thyroid papillary carcinoma to the same cervical lymph node. A 47-year-old man with SCC of the oral tongue at clinical stage T4N1M0 was treated with total glossectomy and bilateral neck dissection. During neck dissection, concomitant secondary foci of thyroid papillary carcinoma were identified in the same cervical lymph node as SCC (collisional metastasis). The patient subsequently underwent total thyroidectomy and was alive without any recurrences at 25 months after the operation.


Assuntos
Carcinoma Papilar/secundário , Carcinoma de Células Escamosas/secundário , Neoplasias Primárias Múltiplas/patologia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Língua/patologia , Glossectomia , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Pescoço , Esvaziamento Cervical , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Neoplasias da Língua/cirurgia
12.
Int J Oral Maxillofac Surg ; 37(12): 1099-105, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18722091

RESUMO

The treatment of oropharyngeal squamous cell carcinoma (OSCC) remains controversial. This study reviews the authors' experience of treating OSCC, evaluates the oncologic outcome and assesses the factors affecting local/regional recurrence. A retrospective analysis of 110 consecutive OSCC patients treated primarily by surgery and/or postoperative radiotherapy was carried out. 82% of patients had advanced disease (stage III or IV). The 5-year overall survival and disease specific survival rates (DSSR) were 58% and 65%, respectively. The DSSR of the soft palate or posterior pharyngeal wall, tonsillar area, and base of tongue were 80%, 62%, and 51%, respectively (P<0.05). The 5-year DSSR according to the American Joint Committee on Cancer stages was 94% for early stage and 56% for advanced stage (P<0.05). The overall recurrence rate was 38% (42 patients). The most frequent site of recurrence was the neck (46%). Only 14% of patients with recurrences were treated successfully. Positive resection margins and the presence of pathologic lymph nodes influenced the recurrence at the primary lesion and in the neck, respectively, in a statistically significant manner. Surgery and postoperative radiotherapy provided a superior outcome in patients with advanced OSCC. A randomized study is required to assess the oncologic and functional superiority of surgery or chemoradiation.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Terapia Neoadjuvante , Neoplasias Orofaríngeas/cirurgia , Adulto , Idoso , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/secundário , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Coreia (Geográfico) , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Pescoço/patologia , Esvaziamento Cervical , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/radioterapia , Palato Mole/efeitos da radiação , Palato Mole/cirurgia , Dosagem Radioterapêutica , Radioterapia Adjuvante , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Neoplasias da Língua/radioterapia , Neoplasias da Língua/cirurgia , Neoplasias Tonsilares/radioterapia , Neoplasias Tonsilares/cirurgia , Resultado do Tratamento
13.
Int J Oral Maxillofac Surg ; 36(7): 610-4, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17344023

RESUMO

To determine the survival rate and analyse the predicting factors of recurrence in patients with unilateral, clinically T2N0 squamous cell carcinoma (SCC) of the tongue which does not cross the midline, a retrospective analysis of 32 such consecutive, previously untreated, cases was performed. All patients were initially treated by surgery between January 1992 and May 2004. All patients had neck dissections: 12 continuous, 20 discontinuous, 24 bilateral and 8 unilateral. Fourteen patients (44%) received adjunctive postoperative radiotherapy. Occult metastatic rates were 34% and 4% in ipsilateral and contralateral neck, respectively. Patients with pN0 cancer had a better 5-year disease-specific survival rate than those with pN+ cancer (85% versus 41%, P=0.005). Twelve patients (38%) had recurrences after the initial treatment. The recurrence rate was significantly higher in patients with pathologic nodal metastasis, peroral resection of the primary tumour or discontinuous neck dissection. The results suggest that the most effective surgical methods for treating unilateral T2N0 SCC of the tongue which does not cross the midline are: pull-through approach for primary lesion instead of peroral approach; continuous rather than discontinuous neck dissection and ipsilateral elective rather than bilateral routine elective neck dissection.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Neoplasias da Língua/cirurgia , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Procedimentos Cirúrgicos Eletivos , Feminino , Seguimentos , Previsões , Humanos , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Esvaziamento Cervical , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Primárias Desconhecidas/patologia , Radioterapia Adjuvante , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Neoplasias da Língua/patologia , Resultado do Tratamento
14.
Oncogenesis ; 6(5): e336, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28504693

RESUMO

High-grade glioma (HGG) is an incurable brain cancer. The transcriptomes of cells within HGG tumors are highly heterogeneous. This renders the tumors unresponsive or able to adapt to therapeutics targeted at single pathways, thereby causing treatment failure. To overcome this, we focused on cyclin-dependent kinase 7 (CDK7), a ubiquitously expressed molecule involved in two major drivers of HGG pathogenesis: cell cycle progression and RNA polymerase-II-based transcription. We tested the activity of THZ1, an irreversible CDK7 inhibitor, on patient-derived primary HGG cell lines and ex vivo HGG patient tissue slices, using proliferation assays, microarray analysis, high-resolution respirometry, cell cycle analysis and in vivo tumor orthografts. The cellular processes affected by CDK7 inhibition were analyzed by reverse transcriptase-quantitative PCR, western blot, flow cytometry and immunofluorescence. THZ1 perturbed the transcriptome and disabled CDK activation, leading to cell cycle arrest at G2 and DNA damage. THZ1 halted transcription of the nuclear-encoded mitochondrial ribosomal genes, reducing mitochondrial translation and oxidative respiration. It also inhibited the expression of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFR-α), reducing signaling flux through the AKT, extracellular-signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) downstream pathways. Finally, THZ1 disrupted nucleolar, Cajal body and nuclear speckle formation, resulting in reduced cytosolic translation and malfunction of the spliceosome and thus leading to aberrant mRNA processing. These findings indicate that CDK7 is crucial for gliomagenesis, validate CDK7 as a therapeutic target and provide new insight into the cellular processes that are affected by THZ1 and induce antitumor activity.

15.
Med Oncol ; 33(4): 36, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26995223

RESUMO

Circulating tumour cells associated with breast cancer (brCTCs) represent cells that have the capability to establish aggressive secondary metastatic tumours. The isolation and characterization of CTCs from blood in a single device is the future of oncology diagnosis and treatment. The methods of enrichment of CTCs have primarily utilized simple biological interactions with bimodal reporting with biased high purity and low numbers or low purity and high background. In this review, we will discuss the advances in microfluidics that has allowed the use of more complex selection criteria and biological methods to identify CTC populations. We will also discuss a potential new method of selection based on the response of the oncogenic DNA repair pathways within brCTCs. This method would allow insight into not only the oncogenic signalling at play but the chemoresistance mechanisms that could guide future therapeutic intervention at any stage of disease progression.


Assuntos
Técnicas Biossensoriais/métodos , Neoplasias da Mama/patologia , Células Neoplásicas Circulantes/patologia , Técnicas Biossensoriais/instrumentação , Neoplasias da Mama/sangue , Quebras de DNA de Cadeia Dupla , Molécula de Adesão da Célula Epitelial/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Dispositivos Lab-On-A-Chip
16.
Oncogene ; 34(18): 2317-24, 2015 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-24954502

RESUMO

Cancer stem cells (CSCs) have been suggested as responsible for the initiation and progression of cancers. Octamer-binding transcription factor 4 (Oct4) is an important regulator of embryonic stem cell fate. Here, we investigated whether Oct4 regulates stemness of head and neck squamous carcinoma (HNSC) CSCs. Our study showed that ectopic expression of Oct4 promotes tumor growth through cyclin E activation, increases chemoresistance through ABCC6 expression and enhances tumor invasion through slug expression. Also, Oct4 dedifferentiates differentiated HNSC cells to CSC-like cells. Furthermore, Oct4(high) HNSC CSCs have more stem cell-like traits compared with Oct4(low) cells, such as self-renewal, stem cell markers' expression, chemoresistance, invasion capacity and xenograft tumorigeneity in vitro and in vivo. In addition, knockdown of Oct4 led to markedly lower HNSC CSC stemness. Finally, there was a significant correlation between Oct4 expression and survival of 119 HNSC patients. Collectively, these data suggest that Oct4 may be a critical regulator of HNSC CSCs and its targeting may be potentially valuable in the treatment of HNSC CSCs.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Células-Tronco Neoplásicas/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Animais , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Ciclina E/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Camundongos , Camundongos Nus , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Invasividade Neoplásica , Transplante de Neoplasias , Fator 3 de Transcrição de Octâmero/genética , Fatores de Transcrição da Família Snail , Análise de Sobrevida , Fatores de Transcrição/metabolismo
17.
Cell Death Differ ; 22(9): 1517-25, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25721045

RESUMO

Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared with the differentiated progeny cells. LMO2 is required for GSC proliferation both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse premalignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in GBMs.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Glioblastoma/irrigação sanguínea , Glioblastoma/patologia , Proteínas com Domínio LIM/biossíntese , Proteínas com Domínio LIM/genética , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Animais , Apoptose/fisiologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Glioblastoma/genética , Glioblastoma/metabolismo , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo
18.
Ann N Y Acad Sci ; 902: 288-93, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10865849

RESUMO

In summary, our findings indicate that specific chemokines that are elaborated by endothelial cells after cytokine or endotoxin activation can play an essential role in monocyte recruitment beyond their chemoattractant activities. We show that this action is to translate initial monocyte tethering into firm adhesion via rapid leukocyte integrin activation. The in vitro model presented here provides a sensitive system for investigating the modulating ability of chemokines and reveals an important biological effect that is not predicted by results in simpler in vitro assays, such as measurement of calcium transients or chemotaxis. The surprising finding that the C-X-C chemokine IL-8 can trigger monocyte firm adhesion to vascular endothelium suggests a potential role for this chemokine in monocyte recruitment and underscores the biological complexity of the chemokine family.


Assuntos
Adesão Celular/fisiologia , Quimiocinas CC/fisiologia , Quimiocinas CXC/fisiologia , Quimiotaxia de Leucócito , Endotélio Vascular/fisiologia , Monócitos/fisiologia , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Selectina E/farmacologia , Selectina E/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Veias Umbilicais , Molécula 1 de Adesão de Célula Vascular/farmacologia , Molécula 1 de Adesão de Célula Vascular/fisiologia
19.
Ann Thorac Surg ; 43(6): 634-8, 1987 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3592833

RESUMO

The anatomic and clinical features of 47 patients who were 18 years of age or older at the time of total intracardiac repair for tetralogy of Fallot are reviewed. Twenty (43%) patients had had previous palliative surgery. Of 14 pulmonary-systemic shunts, 9 (64%) remained patent. The location of the ventricular septal defect was infracristal in 90% of patients. The predominant right ventricular outflow tract obstruction was at the infundibulum in 30%; another 64% of patients had combined valvular and infundibular obstruction. Total intracardiac repair was achieved; hospital mortality was 8.5%. Morbidity was minor, and hemorrhage was a significant problem in only 2 patients. Thirty-five patients have been followed from 11 months to 15 years after surgery. There were 4 late deaths; the actuarial 10-year survival rate was 82%.


Assuntos
Tetralogia de Fallot/cirurgia , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/cirurgia , Análise Atuarial , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Masculino , Métodos , Complicações Pós-Operatórias/epidemiologia , Tetralogia de Fallot/mortalidade , Fatores de Tempo
20.
Eur J Surg Oncol ; 30(6): 692-8, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15256246

RESUMO

AIMS: The goal of this study was to investigate the incidence of occult metastasis in perivascular lymph node and nodal recurrence in these nodal pads in squamous cell carcinoma (SCC) of the tongue and floor of mouth. METHODS: We performed a prospective analysis of the incidence of an occult metastasis in the perivascular lymph nodes in 55 patients (41 with an oral tongue carcinoma and 14 with a mouth floor carcinoma) who underwent an elective supraomohyoid neck dissection (SOHND) for SCC of the tongue and floor of mouth, from 1997 to 2002. 99 SOHND procedures were performed as follows: 72 in tongue carcinomas and 27 in the mouth floor carcinomas. RESULT: Clinically occult, but pathologically positive perivascular lymph nodes occurred in four of 72 of the tongue carcinomas and two of 27 of the mouth floor carcinomas. The incidence of the regional recurrence at level I was three of 45. CONCLUSIONS: This preliminary report reveals a small incidence of perivascular lymph-node metastases and the infrequent nodal recurrence in this area after SOHND in early-staged tongue and floor of mouth SCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Esvaziamento Cervical/métodos , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/cirurgia , Traumatismos do Nervo Facial/etiologia , Traumatismos do Nervo Facial/prevenção & controle , Feminino , Humanos , Incidência , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/cirurgia , Pescoço , Esvaziamento Cervical/efeitos adversos , Invasividade Neoplásica , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/cirurgia , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Procedimentos Cirúrgicos Operatórios/métodos
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