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1.
Clin Chim Acta ; 475: 157-163, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29074220

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide, and early diagnosis is vital to improving prognoses. We explored the diagnostic potential of a multiplex autoantibody panel as a biomarker for the detection of CRC by ELISA. METHODS: In total, 192 serum samples (92 CRC and 100 matched controls) were tested against a panel of 12 tumor-associated antigens (TAAs): RPH3AL, RPL36, SLP2, p53, survivin, ANAXA4, SEC61B, CCCAP, NYCO16, NMDAR, PLSCR1, and HDAC5. Individual and combined autoantibody signatures were examined. RESULTS: Compared to individual autoantibody markers, the combinations of TAAs provided better discrimination between tumorous and normal sera. The overall sensitivity of a selected panel of four antibodies (anti-SLP2, -p53, -SEC61B, and -PLSCR1) was 64.1%, with a specificity of 80% that increased to 83.7% when carcinoembryonic antigen (CEA) measurement was added. Furthermore, the sensitivity of the panel of four antibodies for early and advanced stages of CRC was 66.7% and 62%, increasing to 88.3% and 84%, respectively, when CEA was added. CONCLUSIONS: We identified a panel of four antibodies as a promising diagnostic biomarker for the detection of CRC.


Assuntos
Antígenos de Neoplasias/genética , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , Imunoensaio , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/imunologia , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/imunologia , Antígeno Carcinoembrionário/genética , Antígeno Carcinoembrionário/imunologia , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas de Transferência de Fosfolipídeos/genética , Proteínas de Transferência de Fosfolipídeos/imunologia , Prognóstico , Canais de Translocação SEC/genética , Canais de Translocação SEC/imunologia , Sensibilidade e Especificidade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
2.
J Mech Behav Biomed Mater ; 72: 209-218, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28501000

RESUMO

The aim of this study was to develop a biodegradable three-dimensional-printed polylactide (PLA) cage for promoting bony fixation and an antibiotics-embedded poly(d,l)-lactide-co-glycolide (PLGA) nanofibrous membrane for infectious prophylaxis during treating the comminuted metaphyseal fracture in a rabbit femoral model. The in vitro studies included measuring the mechanical properties of the 3D printed cage and determining release activities of vancomycin and ceftazidime from the nanofibers. The in vivo study included comparisons of rabbits of the femoral metaphyseal comminuted fracture treated with or without the combined biodegradable polymers. The results showed that vancomycin and ceftazidime were sustainably detected above the effective levels in the local tissue fluid around the fracture site for 3 weeks. The animal studies showed that rabbits with the 3D cage implantation possessed better cortical integrity, leg length ratio, and maximal bending strengths. The study results indicate that these combined polymers may promote fracture fixation during treating the rabbit femoral metaphyseal comminuted fracture.


Assuntos
Implantes Absorvíveis , Antibacterianos/administração & dosagem , Fraturas do Fêmur/terapia , Fraturas Cominutivas/terapia , Tecidos Suporte , Animais , Ceftazidima/administração & dosagem , Ácido Láctico/análise , Nanofibras/análise , Ácido Poliglicólico/análise , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Coelhos , Vancomicina/administração & dosagem
3.
Oncotarget ; 8(24): 39401-39416, 2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28455959

RESUMO

Great progress has been achieved in the study of the role of TGF-ß signaling in triggering epithelial-mesenchymal transition (EMT) in a variety of cancers; however, the regulation of TGF-ß signaling during EMT in mammary tumor metastasis has not been completely defined. In the present study, we demonstrated that OVOL2, a zinc finger transcription factor, inhibits TGF-ß signaling-induced EMT in mouse and human mammary tumor cells, as well as in mouse tumor models. Data from the Oncomine databases indicated a strong negative relationship between OVOL2 expression and breast cancer progression. Moreover, our experiments revealed that OVOL2 inhibits TGF-ß signaling at multiple levels, including inhibiting Smad4 mRNA expression and inducing Smad7 mRNA expression, blocking the binding between Smad4 and target DNA, and interfering with complex formation between Smad4 and Smad2/3. These findings reveal a novel mechanism that controls the TGF-ß signaling output level in vitro and in vivo. The modulation of these molecular processes may represent a strategy for inhibiting breast cancer invasion by restoring OVOL2 expression.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Transdução de Sinais , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Biomarcadores , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos , Metástase Neoplásica , Prognóstico , Ligação Proteica , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína Smad7/genética , Proteína Smad7/metabolismo , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
4.
Int J Nanomedicine ; 11: 3927-37, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27574423

RESUMO

In this study, we developed biodegradable sheath-core-structured drug-eluting nanofibers for sustainable delivery of antibiotics (vancomycin and ceftazidime) and recombinant human bone morphogenetic protein (rhBMP-2) via electrospinning. To prepare the biodegradable sheath-core nanofibers, we first prepared solutions of poly(d,l)-lactide-co-glycolide, vancomycin, and ceftazidime in 1,1,1,3,3,3-hexafluoro-2-propanol and rhBMP-2 in phosphate-buffered solution. The poly(d,l)-lactide-co-glycolide/antibiotics and rhBMP-2 solutions were then fed into two different capillary tubes controlled by two independent pumps for coaxial electrospinning. The electrospun nanofiber morphology was observed under a scanning electron microscope. We further characterized the in vitro antibiotic release from the nanofibers via high-performance liquid chromatography and that of rhBMP-2 via enzyme-linked immunosorbent assay and alkaline phosphatase activity. We showed that the biodegradable coaxially electrospun nanofibers could release high vancomycin/ceftazidime concentrations (well above the minimum inhibition concentration [MIC]90) and rhBMP-2 for >4 weeks. These experimental results demonstrate that novel biodegradable nanofibers can be constructed with various pharmaceuticals and proteins for long-term drug deliveries.


Assuntos
Antibacterianos/farmacologia , Materiais Biocompatíveis/química , Proteína Morfogenética Óssea 2/farmacologia , Sistemas de Liberação de Medicamentos , Ácido Láctico/química , Nanofibras/química , Ácido Poliglicólico/química , Animais , Ceftazidima/farmacologia , Liberação Controlada de Fármacos , Humanos , Testes de Sensibilidade Microbiana , Nanofibras/ultraestrutura , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Resistência à Tração , Vancomicina/farmacologia , Água/química
5.
Oncotarget ; 7(25): 37566-37580, 2016 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-27121310

RESUMO

Colorectal cancer (CRC) arises from mutations in a subset of genes. We investigated the germline and somatic mutation spectrum of patients with CRC in Taiwan by using the AmpliSeq Cancer Hotspot Panel V2. Fifty paired freshly frozen stage 0-IV CRC tumors and adjacent normal tissue were collected. Blood DNA from 20 healthy donors were used for comparison of germline mutations. Variants were identified using an ion-torrent personal genomic machine and subsequently confirmed by Sanger sequencing or pyrosequencing. Five nonsynonymous germline variants on 4 cancer susceptible genes, CDH1, APC, MLH1, and NRAS, were observed in 6 patients with CRC (12%). Among them, oncogene NRAS G138R variant was identified as having a predicted damaging effect on protein function, which has never been reported by other laboratories. CDH1 T340A variants were presented in 3 patients. The germline variants in the cancer patients differed completely from those found in asymptomatic controls. Furthermore, a total of 56 COSMIC and 21 novel somatic variants distributed in 20 genes were detected in 44 (88%) of the CRC samples. High inter- and intra-tumor heterogeneity levels were observed. Nine rare variants located in the ß-catenin binding region of the APC gene were discovered, 7 of which could cause amino acid frameshift and might have a pathogenic effect. In conclusion, panel-based mutation detection by using a high-throughput sequencing platform can elucidate race-dependent cancer genomes. This approach facilitates identifying individuals at high risk and aiding the recognition of novel mutations as targets for drug development.


Assuntos
Neoplasias Colorretais/genética , GTP Fosfo-Hidrolases/genética , Genes ras , Mutação em Linhagem Germinativa , Proteínas de Membrana/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Genes APC , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Taiwan
6.
J Orthop Surg Res ; 11(1): 52, 2016 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-27121956

RESUMO

BACKGROUND: Clinical experience and animal studies have suggested that positron emission tomography (PET) using fluorine-18-labeled fluorodeoxyglucose ((18)F-FDG) may be promising for imaging of bone infections. In this study, we aimed to establish the accuracy of (18)F-FDG PET scanning for monitoring the response to poly(lactide-co-glycolide) (PLGA) vancomycin beads for treatment of bone infection. METHODS: PLGA was mixed with vancomycin and hot-compress molded to form antibiotic beads. In vitro, elution assays and bacterial inhibition tests were employed to characterize the released antibiotics. In vivo, cylindrical cavities were made in six adult male New Zealand white rabbits, and Staphylococcus aureus or saline was injected into the cavity to create a bone infection. After 2 weeks, the infection was confirmed by bacterial cultures, and the defect was filled with PLGA vancomycin beads. The treatment response was monitored by (18)F-FDG PET. RESULTS: The biodegradable beads released high concentrations of vancomycin (well above the breakpoint sensitivity concentration) for treatment of bone infection. In bacterial inhibition tests, the diameter of the sample inhibition zone ranged from 6.5 to 10 mm, which was equivalent to 12.5-100 % relative activity. (18)F-FDG PET results showed that uncomplicated bone healing was associated with a temporary increase in (18)F-FDG uptake at 2 weeks, with return to near baseline at 6 weeks. In the infected animals, localized infection resulted in intense continuous uptake of (18)F-FDG, which was higher than that in uncomplicated healing bones. Bone infection was confirmed with positive bacterial cultures. In vancomycin-treated animals, data showed rapidly decreasing amounts of (18)F-FDG uptake after treatment. CONCLUSIONS: In vitro and in vivo analyses showed that the use of biodegradable PLGA vancomycin beads successfully eradicated S. aureus infection in damaged bone.


Assuntos
Antibacterianos/administração & dosagem , Osteomielite/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/administração & dosagem , Implantes Absorvíveis , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos/métodos , Implantes de Medicamento , Fluordesoxiglucose F18 , Masculino , Testes de Sensibilidade Microbiana , Osteomielite/diagnóstico por imagem , Osteomielite/microbiologia , Poliglactina 910 , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tomografia por Emissão de Pósitrons , Coelhos , Infecções Estafilocócicas/diagnóstico por imagem , Vancomicina/farmacologia
7.
J Cancer ; 7(6): 650-5, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27076845

RESUMO

Over the past decade, the emergence of microRNA (miRNA) research has firmly established this molecular family as a key component in cells. MiRNAs, which function as negative gene regulators, participate in multiple biological processes and maintain homeostasis in cells. The dysregulation of miRNA may contribute to numerous human disorders, including cancer. Recently, miR-196 was found to be aberrantly expressed in a wide range of malignant diseases, which suggests that it plays important roles in carcinogenesis. Here, we summarize the current knowledge concerning miR-196 family in cancers. This review includes miR-196 gene structure and aberrant expression in various cancers, and current understanding of numerous functions and regulatory targets of miR-196 in specific cancers. Since miR-196 are consistently found over-expressed in digestive tract cancer tissues, we also reviewed the clinical significance and potential applications of miR-196 in these cancers. We highlight that miR-196 may serve as an emerging cancer biomarker for digestive tract cancers.

8.
Oncotarget ; 7(9): 10663-75, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26848774

RESUMO

Aberrant levels of circulating miRNAs are potential biomarkers for the early detection of colorectal cancer (CRC). However, no previous systematic study has examined miRNAs in various specimen types from the same patient to evaluate their clinical utility. In this study, we compiled information from ~450 articles published before 2012, and selected the 46 most frequently reported CRC-related miRNAs as candidates. We then established a 46-miRNA multiplex RT-qPCR method, and efficiently examined two clinically accessible samples: stool from fecal occult blood test and EDTA plasma. A total of 62 tissue, 447 stool, and 398 plasma samples were collected from CRC patients and healthy controls. Good correlations of detectable miRNAs were noticed in paired tumor tissues, stool, and plasma samples of 62 CRC patients. Using these 62 CRC patients and 62 matched healthy controls as the training set, 5 and 11 differentially expressed miRNAs achieved the area under the ROC curve (AUC) greater than 0.7 in stool and plasma samples, respectively. The selected miRNAs was subsequently validated using the remaining enrolled samples as the test cohort; 4 miRNAs in stool and 6 miRNAs in plasma were maintained discriminating powers for CRC patients. After examining the complementary effect, combined analysis of miR-223 and miR-92a, which were commonly present in stool and plasma samples, yielded the highest sensitivity of 96.8% and the specificity of 75% for CRC (AUC = 0.907). These results allowed us to establish a two-miRNA biosignature in two types of CRC clinical specimens with a high sensitivity for CRC detection.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , MicroRNAs/sangue , Sangue Oculto , Adulto , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos
9.
Gastroenterology ; 150(3): 659-671.e16, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26619963

RESUMO

BACKGROUND & AIMS: Activation of WNT signaling promotes the invasive activities of several types of cancer cells, but it is not clear if it regulates the same processes in colorectal cancer (CRC) cells, or what mechanisms are involved. We studied the expression and function of OVOL2, a member of the Ovo family of conserved zinc-finger transcription factors regulated by the WNT signaling pathway, in intestinal tumors of mice and human beings. METHODS: We analyzed the expression of OVOL2 protein and messenger RNA in CRC cell lines and tissue arrays, as well as CRC samples from patients who underwent surgery at Xiamen University in China from 2009 to 2012; clinical information also was collected. CRC cell lines (SW620) were infected with lentivirus expressing OVOL2, analyzed in migration and invasion assays, and injected into nude mice to assess tumor growth and metastasis. Tandem affinity purification was used to purify the OVOL2-containing complex from CRC cells; the complex was analyzed by liquid chromatography, tandem mass spectrometry, and immunoprecipitation experiments. Gene promoter activities were measured in luciferase reporter assays. We analyzed mice with an intestine-specific disruption of Ovol2 (Ovol2(flox/+) transgenic mice), as well as Apc(min/+) mice; these mice were crossed and analyzed. RESULTS: Analysis of data from patients indicated that the levels of OVOL2 messenger RNA were significantly lower in colon carcinomas than adenomas, and decreased significantly as carcinomas progressed from grades 2 to 4. Immunohistochemical analysis of a tissue array of 275 CRC samples showed a negative association between tumor stage and OVOL2 level. Overexpression of OVOL2 in SW620 cells decreased their migration and invasion, reduced markers of the epithelial-to-mesenchymal transition, and suppressed their metastasis as xenograft tumors in nude mice; knockdown of OVOL2 caused LS174T cells to transition from epithelial to mesenchymal phenotypes. OVOL2 bound T-cell factor (TCF)4 and ß-catenin, facilitating recruitment of histone deacetylase 1 to the TCF4-ß-catenin complex; this inhibited expression of epithelial-to-mesenchymal transition-related genes regulated by WNT, such as SLUG, in CRC cell lines. OVOL2 was a downstream target of WNT signaling in LS174T and SW480 cells. The OVOL2 promoter was hypermethylated in late-stage CRC specimens from patients and in SW620 cells; hypermethylation resulted in OVOL2 down-regulation and an inability to inhibit WNT signaling. Disruption of Ovol2 in Apc(min/+) mice increased WNT activity in intestinal tissues and the formation of invasive intestinal tumors. CONCLUSIONS: OVOL2 is a colorectal tumor suppressor that blocks WNT signaling by facilitating the recruitment of histone deacetylase 1 to the TCF4-ß-catenin complex. Strategies to increase levels of OVOL2 might be developed to reduce colorectal tumor progression and metastasis.


Assuntos
Movimento Celular , Neoplasias Colorretais/metabolismo , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Células CACO-2 , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Regulação para Baixo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Genótipo , Células HCT116 , Células HEK293 , Histona Desacetilase 1/metabolismo , Humanos , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Invasividade Neoplásica , Metástase Neoplásica , Fenótipo , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Fatores de Tempo , Fator de Transcrição 4 , Fatores de Transcrição/genética , Transfecção , Carga Tumoral , beta Catenina/metabolismo
10.
J Virol Methods ; 212: 8-11, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25446515

RESUMO

Human papillomavirus (HPV) types 16 and 18 are known to be high-risk viruses that cause cervical cancer. An HPV rapid testing kit that could help physicians to make early and more informed decisions regarding patient care is needed urgently but not yet available. This study aimed to develop a multiplex nested polymerase chain reaction-immunochromatographic test (PCR-ICT) for the rapid identification of HPV 16 and 18. A multiplex nested PCR was constructed to amplify the HPV 16 and 18 genotype-specific L1 gene fragments and followed by ICT which coated with antibodies to identify rapidly the different PCR products. The type-specific gene regions of high-risk HPV 16 and 18 could be amplified successfully by multiplex nested PCR at molecular sizes of approximately 99 and 101bp, respectively. The capture antibodies raised specifically against the moleculars labeled on the PCR products could be detected simultaneously both HPV 16 and 18 in one strip. Under optimal conditions, this PCR-ICT assay had the capability to detect HPV in a sample with as low as 100 copies of HPV viral DNA. The PCR-ICT system has the advantage of direct and simultaneous detection of two high-risk HPV 16 and 18 DNA targets in one sample, which suggested a significant potential of this assay for clinical application.


Assuntos
Cromatografia de Afinidade/métodos , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Reação em Cadeia da Polimerase Multiplex/métodos , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase/métodos , Humanos , Sensibilidade e Especificidade
11.
Int J Nanomedicine ; 9: 4347-55, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25246790

RESUMO

We developed biodegradable drug-eluting nanofiber-enveloped implants that provided sustained release of vancomycin and ceftazidime. To prepare the biodegradable nanofibrous membranes, poly(D,L)-lactide-co-glycolide and the antibiotics were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. They were electrospun into biodegradable drug-eluting membranes, which were then enveloped on the surface of stainless plates. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vivo and in vitro release rates of the antibiotics from the nanofiber-enveloped plates. The results showed that the biodegradable nanofiber-enveloped plates released high concentrations of vancomycin and ceftazidime (well above the minimum inhibitory concentration) for more than 3 and 8 weeks in vitro and in vivo, respectively. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The bioactivity ranged from 25% to 100%. In addition, the serum creatinine level remained within the normal range, suggesting that the high vancomycin concentration did not affect renal function. By adopting the electrospinning technique, we will be able to manufacture biodegradable drug-eluting implants for the long-term drug delivery of different antibiotics.


Assuntos
Antibacterianos/farmacocinética , Ceftazidima/farmacocinética , Portadores de Fármacos/farmacocinética , Nanofibras/química , Vancomicina/farmacocinética , Implantes Absorvíveis , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Materiais Biocompatíveis/farmacologia , Ceftazidima/química , Ceftazidima/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Portadores de Fármacos/toxicidade , Técnicas Eletroquímicas , Viabilidade Microbiana/efeitos dos fármacos , Nanofibras/toxicidade , Nanotecnologia , Coelhos , Staphylococcus aureus , Vancomicina/química , Vancomicina/farmacologia , Vancomicina/toxicidade
12.
Med Oncol ; 31(8): 79, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24961465

RESUMO

Survivin, a structurally unique protein expressed in most common human neoplasms, is thought to support cell cycle progression and suppress apoptosis. Survivin expression is highly correlated with advanced non-small cell lung cancer (NSCLC) and poor prognosis. In this retrospective study of banked pathology tissue of patients with advanced NSCLC, we tested for correlations of N-survivin expression in tumor tissues and responsiveness to treatment with platinum-based regimens containing paclitaxel or docetaxel. The 48 patients with NSCLC included 32 (66.7 %) males and 16 (33.3 %) females. Mean age at diagnosis was 59.4 years (range 36-83 years), and median follow-up time was 20.4 months (range 3.4-59.0 months). Patients with high tumor N-survivin expression had significantly better responses to taxane-platinum chemotherapy than those with low tumor N-survivin expression (P < 0.001). Adjusted multivariate modeling found high tumor N-survivin expression to be an independent prognostic factor for a clinical response to chemotherapy (high vs. low, OR 6.14, 95 % CI 1.62-23.29; P = 0.008). Median overall survival differed significantly between those with high tumor N-survivin expression who did/did not respond to chemotherapy and between those with low tumor N-survivin expression who did/did not respond to chemotherapy (P < 0.05). Tumor N-survivin expression shows promise as a predictive biomarker in the chemotherapy setting as a surrogate marker of high proliferation status.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Docetaxel , Feminino , Humanos , Proteínas Inibidoras de Apoptose/análise , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Valor Preditivo dos Testes , Prognóstico , Survivina , Taxoides/administração & dosagem , Resultado do Tratamento
13.
Chem Biol Drug Des ; 84(1): 36-43, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24766818

RESUMO

Phospholipid scramblase 1 involve in biological processes including phospholipid movement, proliferation, and apoptosis. Treatment with an antiphospholipid scramblase 1 antibody (NP1) has been demonstrated to inhibit cell proliferation in colorectal cancer. This study aimed to explore the role of NP1 treatment in the apoptosis of colorectal cancer cells. Results showed that NP1 treatment significantly increases the apoptosis of colorectal cancer cells via the activation of caspase 8, caspase 9, and caspase 3. Moreover, pretreatment with a caspase 8 inhibitor did not fully prevent the apoptotic effects of NP1. Taken together, these data indicate NP1 induces cell apoptosis primary through the intrinsic apoptotic pathway. NP1 may serve as a potential therapeutic agent.


Assuntos
Anticorpos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Terapia de Alvo Molecular , Proteínas de Transferência de Fosfolipídeos/metabolismo , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Colo/efeitos dos fármacos , Colo/enzimologia , Colo/patologia , Neoplasias Colorretais/patologia , Humanos , Proteínas de Transferência de Fosfolipídeos/química , Estrutura Terciária de Proteína/efeitos dos fármacos , Reto/efeitos dos fármacos , Reto/enzimologia , Reto/patologia
14.
Clin Chim Acta ; 433: 284-9, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24685572

RESUMO

Colorectal cancer (CRC) patients with KRAS mutations do not benefit from epidermal growth factor receptor (EGFR) targeted therapy. In clinical practice, identifying patients with KRAS mutations is critical prior to EGFR targeting therapy, and gene testing is generally performed using the DNA extracted from tumor tissue. The aim of this study was to compare the presence of KRAS mutations in circulating cell-free DNA (cfDNA) and primary tumor tissue using a peptide nucleic acid mediated polymerase chain reaction. We extracted and analyzed the DNA from plasmas and corresponding primary tumor samples from 52 patients with CRC. The results demonstrated that the detection rate of KRAS sequence variations was 50% (26 of 52) in plasma samples and 28.8% (15 of 52) in resected primary tumor tissue samples. The majority of KRAS mutations detected in tumors were also found in matched plasma specimens with an agreement rate of 78.8%. Eleven plasma cfDNA were found positive for KRAS mutation but not in their corresponding tissue. In conclusion, our results suggest that circulating cfDNA provides a better representation of the malignant disease as a whole and could be a reliable source of diagnostic DNA to replace the tumor tissue in a diagnostic setting.


Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Análise Mutacional de DNA , DNA/sangue , DNA/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas p21(ras)
15.
Clin Chem Lab Med ; 51(6): 1291-300, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23154424

RESUMO

BACKGROUND: Oral cavity cancer ranks as the fourth leading cancer in men in Taiwan. The development of a serum biomarker panel for early detection and disease monitoring is, therefore, warranted. METHODS: Nine inflammation-associated markers were investigated in 46 patients with leukoplakia, 151 patients with untreated oral cavity squamous cell carcinoma (OSCC), and 111 age- and gender-matched healthy controls using enzyme-linked immunosorbent assay. During a subsequent 28-month surveillance of OSCC patients, serum samples were prospectively collected at predetermined intervals following the completion of therapy. RESULTS: Logistic regression analysis showed matrix metalloproteases (MMP)-2, MMP-9, C-reactive protein (CRP), transforming growth factor-ß1 (TGF-ß1), and E-selectin having the best discrimination power between groups and significant elevation trends of those five markers were noted from control to OSCC. By combining those five markers, a 0.888 and 0.938 area under curve by ROC curve analysis with 67.4% and 80% overall sensitivity and fixed 90% specificity for leukoplakia and OSCC groups were demonstrated. In the follow-up period, 25 OSCC patients developed recurring or secondary tumors. All examined markers had decreased in relapse-free patients following treatment. However, in patients with relapse, interleukin-6, CRP, and serum amyloid A remained at elevated levels. Statistical analysis showed that patients with CRP ≧2 mg/L and E-selectin ≧85 ng/mL at baseline had highest probability of relapse (odds ratio=3.029, p<0.05). CONCLUSIONS: The results indicate that inflammation plays a crucial role in the pathogenesis process of OSCC. By examining the inflammation markers, physicians could potentially identify patients at risk of cancer transformation or relapse.


Assuntos
Carcinoma de Células Escamosas/sangue , Neoplasias de Cabeça e Pescoço/sangue , Inflamação/sangue , Leucoplasia/sangue , Neoplasias Bucais/sangue , Biomarcadores/sangue , Biomarcadores Tumorais/sangue , Proteína C-Reativa/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Selectina E/sangue , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Inflamação/líquido cefalorraquidiano , Inflamação/patologia , Leucoplasia/diagnóstico , Leucoplasia/patologia , Masculino , Metaloproteinase 9 da Matriz/sangue , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/patologia , Prognóstico , Estudos Prospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fator de Crescimento Transformador beta1/sangue
16.
J Transl Med ; 10: 254, 2012 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-23259795

RESUMO

BACKGROUND: Membrane-bound phospholipid scramblase 1 (PLSCR1) is involved in both lipid trafficking and cell signaling. Previously, we showed that PLSCR1 is overexpressed in many colorectal carcinomas (CRCs). In the present study, we investigated the tumorigenic role of PLSCR1 in CRC and suggest that it is a potential therapeutic target. METHODS: To identify PLSCR1 as a therapeutic target, we studied the tumorigenic properties of CRC cell lines treated with a monoclonal antibody (NP1) against the N-terminus of PLSCR1 in vitro and in vivo. We also investigated cell cycle status and epidermal growth factor receptor-related pathways and downstream effectors of PLSCR1 after blocking its function with NP1. RESULTS: Treating CRC cells with NP1 in vitro and in vivo decreased cell proliferation, anchorage-independent growth, migration, and invasion. Adding NP1 to the CRC cell line HT29 caused arrest at G1/S. Treating HT29 cells with NP1 significantly decreased the expression of cyclin D1 and phosphorylation levels of Src, the adaptor protein Shc, and Erks. The reduced level of cyclin D1 led to an increase in the activated form of the tumor suppressor retinoblastoma protein via dephosphorylation. These actions led to attenuation of tumorigenesis. CONCLUSIONS: Therefore, PLSCR1 may serve as a potential therapeutic target for CRC.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Proteínas de Transferência de Fosfolipídeos/antagonistas & inibidores , Proteínas de Transferência de Fosfolipídeos/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Neoplasias Colorretais/enzimologia , Receptores ErbB/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Proteínas de Transferência de Fosfolipídeos/química , Estrutura Terciária de Proteína , Fase S/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Análise Serial de Tecidos , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Clin Vaccine Immunol ; 19(5): 817-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22398247

RESUMO

An anti-hepatitis delta (HD) enzyme-linked immunosorbent assay (ELISA) using a specific recombinant hepatitis delta antigen derived from a local dominant hepatitis delta virus (hepatitis D virus; HDV) strain in Taiwan has been established. The detection efficiency of this assay was comparable to that of the commercially available Abbott anti-HD radioimmunoassay (RIA) and could be useful in routine laboratory diagnoses of HDV infection.


Assuntos
Técnicas de Laboratório Clínico/métodos , Anticorpos Anti-Hepatite/sangue , Hepatite D/diagnóstico , Vírus Delta da Hepatite/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Antígenos da Hepatite delta , Humanos , Radioimunoensaio/métodos , Proteínas Recombinantes , Taiwan
18.
Int J Nanomedicine ; 7: 763-71, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22359454

RESUMO

BACKGROUND: The purpose of this study was to develop novel sandwich-structured nanofibrous membranes to provide sustained-release delivery of vancomycin, gentamicin, and lidocaine for repair of infected wounds. METHODS: To prepare the biodegradable membranes, poly(D, L)-lactide-co-glycolide (PLGA), collagen, and various pharmaceuticals, including vancomycin, gentamicin, and lidocaine, were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. They were electrospun into sandwich-structured membranes with PLGA/collagen as the surface layers and PLGA/drugs as the core. An elution method and a high-pressure liquid chromatography assay were used to characterize in vivo and in vitro drug release from the membranes. In addition, repair of infected wounds in rats was studied. Histological examination of epithelialization and granulation at the wound site was also performed. RESULTS: The biodegradable nanofibrous membranes released large amounts of vancomycin and gentamicin (well above the minimum inhibition concentration) and lidocaine in vivo for more than 3 weeks. A bacterial inhibition test was carried out to determine the relative activity of the antibiotics released. The bioactivity ranged from 40% to 100%. The nanofibrous membranes were functionally active in treating infected wounds, and were very effective as accelerators in early-stage wound healing. CONCLUSION: Using the electrospinning technique, we will be able to manufacture biodegradable, biomimetic, nanofibrous, extracellular membranes for long-term delivery of various drugs.


Assuntos
Bandagens , Preparações de Ação Retardada/farmacologia , Membranas Artificiais , Nanofibras/química , Cicatrização/efeitos dos fármacos , Análise de Variância , Animais , Lesões nas Costas/tratamento farmacológico , Lesões nas Costas/patologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Técnicas Eletroquímicas , Gentamicinas/química , Gentamicinas/farmacocinética , Gentamicinas/farmacologia , Histocitoquímica , Lidocaína/química , Lidocaína/farmacocinética , Lidocaína/farmacologia , Ratos , Ratos Sprague-Dawley , Vancomicina/química , Vancomicina/farmacocinética , Vancomicina/farmacologia , Cicatrização/fisiologia
19.
AAPS PharmSciTech ; 12(4): 1110-5, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21879391

RESUMO

This paper developed solvent-free drug-eluting implants for metronidazole delivery for the treatment of periodontal disease and investigated the characteristics of the drug's release from the implants, both in vitro and in vivo, using an HPLC assay. The metronidazole exhibited a two-stage release behavior in vitro with an initial burst release followed by a diffusion-controlled release and then a secondary burst release. The accumulated drug release reached 100% on the 18th day, and the drug-eluting implant was totally dissolved on the same day. Additionally, the drug-eluting disks were implanted within the sub-gingival space of both lower incisors of six rabbits. The curve of in vivo drug release was smoother and showed a predominantly diffusion-controlled release. The implants were totally dissolved at 2 weeks after implantation. The concentration of metronidazole remained above the MIC(90) during the entire investigation.


Assuntos
Implantes Absorvíveis , Anti-Infecciosos/administração & dosagem , Materiais Revestidos Biocompatíveis , Portadores de Fármacos , Ácido Láctico/química , Metronidazol/administração & dosagem , Doenças Periodontais/tratamento farmacológico , Ácido Poliglicólico/química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Difusão , Composição de Medicamentos , Metronidazol/química , Metronidazol/farmacocinética , Testes de Sensibilidade Microbiana , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Desenho de Prótese , Coelhos , Solubilidade , Tecnologia Farmacêutica/métodos
20.
Clin Chim Acta ; 412(15-16): 1417-22, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21536019

RESUMO

BACKGROUND: Rabphilin-3A-like (RPH3AL) protein functions in the regulation of hormone exocytosis, and mutations in the RPHA3L gene have been associated with tumorigenesis in colorectal cancer (CRC). We evaluated the potential use of anti-RPH3AL autoantibodies as a marker for CRC detection. METHODS: Sera from 84 patients with CRC and 63 healthy controls were analysed for the presence of RPH3AL autoantibodies with a Western blotting assay. RESULTS: The frequencies of RPH3AL autoantibodies in the early stage, advanced stage and all CRC patients were 64.7%, 78.0% and 72.6%, respectively. These values are significantly higher than the frequency of RPH3AL autoantibodies in healthy controls (15.9%, P<0.001). Although the presence of RPH3AL autoantibodies did not correlate with clinical parameters, RPH3AL autoantibodies were found in 69.4% (34/49) of CRC patients who were negative for carcinoembryonic antigen. The value of the area under the receiver operating characteristic curve of RPH3AL autoantibody was 0.84, which suggests that screening for these autoantibodies could potentially be used for CRC diagnosis. CONCLUSION: Circulating RPH3AL autoantibodies are prevalent in patients with CRC, and detection of these autoantibodies might provide a novel non-invasive approach for CRC diagnosis.


Assuntos
Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Proteínas rab de Ligação ao GTP/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Recombinantes/sangue , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/isolamento & purificação
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