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1.
Int J Cancer ; 130(5): 1230-5, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21455991

RESUMO

Expression of microRNAs can affect age of tumor onset and prognosis of cancer patients. However, nothing is known about the effects of microRNAs on altered age of cancer onset and disease-specific survival of soft-tissue sarcoma (STS) patients. The levels of miR-210, also known as hypoxia-regulated microRNA, were analyzed by quantitative real-time (RT)-PCR in the tumors of 78 STS patients. The patients were stratified according to their microRNA levels with low, intermediate and high expression levels and the association of microRNA expression and patients' survival was analyzed using multivariate Cox's regression hazard analyses. A significant correlation between an intermediate miR-210 expression and disease-specific death of STS patients [relative risk (RR) = 3.19; p = 0.018] was observed compared with patients with high expression levels in their tumors. Interestingly, the association between an intermediate expression of miR-210 and a poor prognosis was only significant in female STS patients (RR = 11.28; p = 0.010), but not observed in male individuals. Furthermore, the expression of miR-210 showed a significant association with the age of tumor onset in a gender-specific manner. Specifically, male patients with an intermediate expression of miR-210 associated with a 9.6-year later age of tumor onset (p = 0.017) compared with males with a low expression of miR-210 in their tumors. However, no significant differences in the female patients were observed. This study provides the first evidence of a correlation of expression levels of a single microRNA (miR-210) with the prognosis and age of tumor onset in a gender-specific manner in STS patients.


Assuntos
Idade de Início , MicroRNAs/metabolismo , Sarcoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sarcoma/mortalidade
2.
Br J Cancer ; 102(4): 731-7, 2010 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-20051950

RESUMO

BACKGROUND: The urokinase plasminogen activator (uPA) system is one of the best-investigated protease systems, both under physiological and pathological conditions, including various types of cancer. However, effects of co-expression of members of the uPA system in soft-tissue sarcoma (STS) patients at the protein level in both tumour tissue and serum have not been investigated yet. METHODS: We examined 82 STS patients for protein levels of uPA, PAI-1and uPAR in tumour tissue and serum by ELISA. RESULTS: A significant correlation between high antigen levels of uPA, PAI-1 or uPAR in tumour tissue, and of uPAR in serum, with poor outcome of STS patients was found for the first time. Most strikingly, we observed an additive effect of combined uPA, PAI-1 or uPAR levels in tumour tissue extracts with uPAR levels in serum on patients' prognosis. High uPA/uPAR, PAI-1/uPAR and uPAR/uPAR antigen levels in tumour tissue/serum were associated with a 5.9-fold, 5.8-fold and 6.2-fold increased risk of tumour-related death (P=0.003, 0.001 and 0.002, respectively) compared with those patients who displayed low levels of the respective marker combination. CONCLUSION: As expression of members of the uPA system in tumour tissue and serum is additively correlated with prognosis of STS patients, our results suggest that combinations of these biomarkers can identify STS patients with a higher risk of tumour-related death.


Assuntos
Inibidor 1 de Ativador de Plasminogênio/análise , Receptores de Ativador de Plasminogênio Tipo Uroquinase/análise , Sarcoma/diagnóstico , Ativador de Plasminogênio Tipo Uroquinase/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Técnicas e Procedimentos Diagnósticos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Prognóstico , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Sarcoma/sangue , Sarcoma/metabolismo , Sarcoma/mortalidade , Análise de Sobrevida , Ativador de Plasminogênio Tipo Uroquinase/sangue , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Adulto Jovem
3.
J Oral Pathol Med ; 39(4): 313-7, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19780905

RESUMO

BACKGROUND: This study investigates the prognostic impact of the expression of hypoxia-inducible factor 1alpha (Hif1alpha) and carbonic anhydrase IX (CAIX) detected by immunohistochemistry in oral squamous cell carcinoma (OSCC). METHODS: Statistical analysis of immunohistochemical results with clinical parameters including survival outcomes was performed for 80 OSCC patients. RESULTS: Patients with a low expression of both proteins survived on average 54.8 months, whereas those with an increased expression of Hif1alpha in their tumors combined with a low expression of CAIX survived on average only 37.6 months (P = 0.026). In multivariate Cox's regression hazard analysis, again patients with a low expression of Hif1alpha/CAIX had the best prognosis, whereas patients with increased Hif1alpha and low CAIX expression carried a 4.97-fold increased risk of tumor-related death (P = 0.042). CONCLUSION: A co-detection of low Hif1alpha/CAIX expression is significantly correlated with a better prognosis for OSCC patients, which may have implications for therapy options for these patients.


Assuntos
Antígenos de Neoplasias/análise , Anidrases Carbônicas/análise , Carcinoma de Células Escamosas/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Neoplasias Bucais/patologia , Anidrase Carbônica IX , Carcinoma de Células Escamosas/secundário , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores Sexuais , Taxa de Sobrevida
4.
Respiration ; 80(5): 393-400, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20029169

RESUMO

BACKGROUND: Induced sputum is the most commonly used method to analyze airway inflammation in cystic fibrosis (CF) patients ex vivo. Due to the complex matrix of the sample material, precise and reliable analysis of sputum constituents depends critically on preanalytical issues. OBJECTIVES: Here we compared the commonly used method for sputum processing by dithiothreitol (DTT) with a novel mechanical method in regard to basal cellular parameters, neutrophil markers and glutathione (GSH) levels. METHODS: Sputum samples from CF patients were processed in parallel with or without the use of DTT. The key improvement of the mechanical method was the processing in many very small aliquots. Cellular and humoral markers were assessed and compared according to Bland-Altman. RESULTS: Total cell count, cell viability, differential cell count, neutrophil elastase levels and flow cytometrically analyzed neutrophil markers (CD63, CD11b, DHR) did not differ between the two methods. Intracellular and extracellular GSH levels were significantly higher in DTT-treated samples (p = 0.002). CONCLUSION: The mechanical sputum-processing method presented had a similar yield of cells and fluids as the conventional DTT method and the advantage of omitting the introduction of reducing agents. This method allows a more reliable analysis of redox-dependent airway inflammation in sputum cells and fluid from CF patients than methods utilizing DTT.


Assuntos
Fibrose Cística/imunologia , Escarro/metabolismo , Adulto , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Antígeno CD11b/metabolismo , Contagem de Células , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Ditiotreitol , Feminino , Citometria de Fluxo , Glutationa/metabolismo , Humanos , Indicadores e Reagentes , Elastase de Leucócito/metabolismo , Masculino , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores de Interleucina-8A/metabolismo , Rodaminas/metabolismo , Tetraspanina 30
5.
Internist (Berl) ; 50(10): 1213-4, 1216, 1218-20, 2009 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-19714300

RESUMO

During the last 30 years, life expectancy in patients with cystic fibrosis has significantly improved. In Germany, almost half of the 8500 patients are 18 years or older. Older patients have increased rates of cystic fibrosis typical complications, In addition the characteristic complications of adulthood, including arterial hypertension, hyperlipidemia, and cardiovascular diseases, occur. Also crisis of marriage or loss of work place, as well as family planning measures including in-vitro-fertilization are problems merely of the adult cystic fibrosis patient. Therefore adult patients should be treated in a centre specialized on adults. At the moment, in Germany only one third of all adult patients are followed up in an adult center, many patients are treated in age-independent centers, and also a significant number is treated in small clinics. In this article models for transition currently established in Germany are described and occurring problems with their implementation are discussed.


Assuntos
Serviços de Saúde do Adolescente/tendências , Fibrose Cística/diagnóstico , Fibrose Cística/terapia , Atenção à Saúde/tendências , Necessidades e Demandas de Serviços de Saúde/tendências , Transição Epidemiológica , Medicina Interna/tendências , Adolescente , Adulto , Alemanha , Humanos , Adulto Jovem
6.
Oncogene ; 26(7): 1098-100, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16953229

RESUMO

Self-renewal is considered as a common property of stem cells. Dysregulation of stem cell self-renewal is likely a requirement for the development of cancer. Hiwi, the human Piwi gene, encodes a protein responsible for stem cell self-renewal. In this study, we investigated the expression of Hiwi at the RNA level by real-time quantitative PCR in 65 primary soft-tissue sarcomas (STS) and ascertained its impact on prognosis for STS patients. In a multivariate Cox's proportional hazards regression model, we found that an increased expression of Hiwi mRNA is a significant negative prognostic factor for patients with STS (P=0.017; relative risk 4.6, 95% confidence interval (CI) 1.3-16.1) compared to medium expression of Hiwi transcript. However, a low expression of Hiwi transcript is correlated with a 2.4-fold (CI 0.7-8.0) increased risk, but this effect was not significant (P=0.17). Altogether, high-level expression of Hiwi mRNA identifies STS patients at high risk of tumour-related death. This is the first report showing a correlation between expression of a gene involved in stem cell self-renewal and prognosis of cancer patients.


Assuntos
Proteínas/genética , Sarcoma/mortalidade , Células-Tronco/metabolismo , Adulto , Proteínas Argonautas , Feminino , Humanos , Masculino , Prognóstico , Proteínas/metabolismo , RNA Mensageiro/biossíntese , Medição de Risco , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/patologia , Células-Tronco/patologia
7.
Oncogene ; 26(50): 7170-4, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17525744

RESUMO

Cancer stem cells can play an important role in tumorigenesis and tumor progression. However, it is still difficult to detect and isolate cancer stem cells. An alternative approach is to analyse stem cell-associated gene expression. We investigated the coexpression of three stem cell-associated genes, Hiwi, hTERT and survivin, by quantitative real-time-PCR in 104 primary soft-tissue sarcomas (STS). Multivariate Cox's proportional hazards regression analyses allowed correlating gene expression with overall survival for STS patients. Coexpression of all three stem cell-associated genes resulted in a significantly increased risk of tumor-related death. Importantly, tumors of patients with the poorest prognosis were of all four tumor stages, suggesting that their risk is based upon coexpression of stem cell-associated genes rather than on tumor stage.


Assuntos
Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Sarcoma/genética , Sarcoma/patologia , Proteínas Argonautas , Feminino , Humanos , Proteínas Inibidoras de Apoptose , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Prognóstico , Proteínas/genética , Sarcoma/etiologia , Survivina , Telomerase/genética
8.
Curr Med Chem ; 15(4): 322-38, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18288988

RESUMO

Poor oxygenation of solid tumors is a major indicator of adverse prognosis after standard treatment, e.g. radiotherapy. This observation founded on intratumoral pO(2) electrode measurements has been supported more recently by studies of injected hypoxia markers (pimonidazole, EF5) or hypoxia-related proteins (hypoxia-inducible factor-1alpha, carbonic anhydrase IX) detected immunohistochemically. Alternative approaches include imaging of tumor hypoxia by nuclear medicine studies and the measurement of hypoxia-related proteins (osteopontin) in patient plasma. Low oxygen levels as found in tumors are rarely observed in normal tissues. The presence of hypoxic tumor cells is therefore regarded not only as an adverse prognostic factor but as an opportunity for tumor-specific treatment. Classic approaches to normalize tumor oxygenation involve the breathing of modified gas mixtures and pharmacologic modification of blood flow as in the "accelerated radiotherapy, carbogen, nicotinamide" (ARCON) scheme. Specific killing of hypoxic tumor cells can potentially be achieved by hypoxia-selective cytotoxins (model substance tirapazamine), which has shown promise in head and neck cancer. Direct targeting of hypoxia-related molecules such as hypoxia-inducible factor-1alpha, the central regulator of the hypoxic response in tumor cells, is an attractive approach currently tested in preclinical models. For clinical applications, the appropriate combination of hypoxia detection for patient selection with a hypoxia-specific treatment is essential. A therapeutic benefit has been suggested for the selection of patients by plasma osteopontin level and treatment with the hypoxic radiosensitizer nimorazole in addition to radiotherapy, for selection by F-misonidazole positron-emission tomography (PET) and treatment with tirapazamine in addition to chemoradiation and for selection by pimonidazole immunohistochemistry and ARCON treatment, all in head and neck cancer.


Assuntos
Hipóxia/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/radioterapia , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Eletrodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hipóxia/diagnóstico por imagem , Hipóxia/genética , Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Osteopontina/biossíntese , Osteopontina/genética , Oxigênio/química , Tomografia por Emissão de Pósitrons , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico
9.
Eur Respir J ; 32(3): 783-95, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18757703

RESUMO

Progressive lung disease determines the morbidity and mortality of cystic fibrosis (CF) patients. CF lung disease is characterised by endobronchial inflammation sustained by bacterial infections and an ongoing accumulation of airway neutrophils. Activated or necrotic neutrophils liberate proteases that cause damage to structural, cellular and soluble components of the pulmonary microenvironment. Among various proteases released by airway cells, elastase is considered to play the major role in CF lung disease. Based on this concept, several therapeutic approaches have been developed to inhibit free elastolytic activity, including small synthetic chemical compounds, semi-synthetic inhibitors and natural inhibitors of free elastase. The present review summarises and discusses the pathophysiological rationales, methodological requirements and clinical implications of inhibition of airway proteases in cystic fibrosis lung disease.


Assuntos
Brônquios/enzimologia , Fibrose Cística/enzimologia , Elastase de Leucócito/efeitos dos fármacos , Brônquios/fisiopatologia , Ensaios Clínicos como Assunto , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Humanos , Elastase de Leucócito/fisiologia , Inibidores de Proteases/uso terapêutico , alfa 1-Antitripsina/uso terapêutico
10.
Respir Med ; 140: 11-20, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29957271

RESUMO

BACKGROUND: Pulmonary interstitial glycogenosis (PIG) is a rare paediatric interstitial lung disease of unknown cause. The diagnosis can only be made by lung biopsy. Less than 100 cases have been reported. Clinical features, treatment and outcomes have rarely been assessed systematically in decent cohorts of patients. METHODS: In this retrospective multicentre study, the clinical presentation, radiologic findings, pattern of lung biopsy, extrapulmonary comorbidities, treatment and outcome of eleven children with PIG were collected systematically. RESULTS: 10/11 children presented with respiratory distress immediatly after birth and 8/11 needed invasive ventilation. In 8/11 children extrapulmonary comorbidities were present, congenital heart defects being the most common. 7/11 children received systemic glucocorticoids and of these four showed a clear favorable response. During a median follow-up of 3.0 years (range 0.42-12.0) one child died, while 10 patients improved. Chest CT-scans showed ground-glass opacities (7/10), consolidations (6/10), linear opacities (5/10) and mosaic attenuation (4/10) without uniform pattern. Besides interstitial thickening related to undifferentiated glycogen positive mesenchymal cells all tissue samples showed growth abnormalities with reduced alveolarization. CONCLUSIONS: PIG is associated with alveolar growth abnormalities and has to be considered in all newborns with unexplained respiratory distress. Apparent treatment benefit of glucocorticosteroids needs to be evaluated systematically.


Assuntos
Doença de Depósito de Glicogênio/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Biópsia , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Idade Gestacional , Glucocorticoides/administração & dosagem , Doença de Depósito de Glicogênio/tratamento farmacológico , Doença de Depósito de Glicogênio/patologia , Humanos , Lactente , Pulmão/patologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Masculino , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Doenças Raras/patologia , Sistema de Registros , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
11.
Int J Oncol ; 30(6): 1317-24, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17487351

RESUMO

In order to reduce side effects of survivin-inhibiting anticancer therapies, we determined the expression of the survivin transcripts survivin-wild-type (survivin-wt), survivin-DeltaEx3 (DeltaEx3) and survivin-2B (2B) in cryo-preserved tumor and non-malignant bladder tissues (18 tumor and 22 non-malignant samples, including 17 autologous tissue pairs) by quantitative PCR. Furthermore, we investigated the biological effects following specific inhibition of the alternative transcripts DeltaEx3 and 2B in bladder cancer (BCa) cells. In BCa and non-malignant bladder tissues survivin-wt was the quantitatively dominant transcript followed by DeltaEx3 and 2B. The mean mRNA expression of DeltaEx3 (0.37 vs. 0.06 zmol/amol GAPDH, respectively) and 2B (0.13 vs. 0.01 zmol/amol GAPDH, respectively) was significantly higher in BCa compared to non-malignant bladder tissues, indicating their accessibility for an expression inhibition in BCa cells. Effective and long-lasting small interfering RNA-mediated inhibition of one alternative survivin transcript caused lower cell growth reduction effects (apoptosis induction, cell cycle arrest, colony formation) compared to simultaneous inhibition of multiple survivin transcripts including survivin-wt. Inhibition of one alternative survivin transcript increased the apoptosis rate by 11% vs. 33-46% when reducing several survivin transcripts. We observed no G2/M arrest or reduction of cell colony formation after inhibiting one alternative survivin transcript. Reduction of cell viability by the chemotherapeutics cisplatin, mitomycin C or gemcitabine was stronger in combination with inhibition of several survivin transcripts than in combination with the reduction of one alternative survivin splice variant. Furthermore, reducing one alternative transcript caused chemosensitization to only one chemotherapeutic agent in contrast to inhibition of several survivin transcripts. Therefore, the alternative survivin transcripts DeltaEx3 and 2B do not represent reasonable targets for anticancer, at least BCa, treatment.


Assuntos
Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/biossíntese , RNA Interferente Pequeno , Neoplasias da Bexiga Urinária/metabolismo , Processamento Alternativo , Antineoplásicos/farmacologia , Apoptose/fisiologia , Western Blotting , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Proteínas Inibidoras de Apoptose , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Proteínas de Neoplasias/efeitos dos fármacos , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Survivina
12.
Leukemia ; 17(12): 2444-53, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14562117

RESUMO

Marrow fibrosis (MF) has rarely been considered in therapy studies on chronic myeloid leukemia (CML), and there is a lack of long-term observations on the basis of sequential bone marrow biopsies (BMBs) taken prospectively during the course of disease. A total of 848 BMBs from 400 patients with Ph(+) CML recruited in the German randomized CML study I were examined for MF before and during therapy. In total, 110 patients had been randomized to receive interferon (IFN)-alpha, and 290 to receive chemotherapy (hydroxyurea (HU): 154, busulfan: 136). During IFN-alpha and HU medication, MF was reduced or did not increase for about 2 years. Evolving or progressive MF was an independent and early predictor of therapy failure about 2 years earlier than indicated by changes in the peripheral blood, spleen size, marrow blast count and cytogenetics (P<0.00005), resulting in a significant shortening of the survival times of patients independent of the type of therapy applied including allografting (multivariate analyses; P<0.00005). The analyzed long-term observations strongly indicate that MF is an independent poor prognostic complication of CML, allowing an early prediction of therapy failure. Consideration of the fiber content in marrow may therefore significantly improve the prediction of therapy efficacy and outcome of disease.


Assuntos
Antineoplásicos/administração & dosagem , Medula Óssea/patologia , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Biópsia , Transplante de Medula Óssea , Bussulfano/administração & dosagem , Aberrações Cromossômicas , Resistencia a Medicamentos Antineoplásicos , Feminino , Fibrose , Seguimentos , Humanos , Hidroxiureia/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida , Falha de Tratamento
13.
Eur J Med Res ; 10(8): 345-51, 2005 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-16131476

RESUMO

RATIONALE AND GOALS: Infections of the respiratory tract with multiresistant bacteria and other pathogens lead to a poor prognosis in patients with cystic fibrosis. The patient-to-patient transmission of infectious agents during the clinic visit and the transmission via the hands of healthcare workers has gained increased attention in the cystic fibrosis community. For this reason practical and possibly evidence-based instructions for infection control measures are needed that are feasible in every day outpatient management of patients with cystic fibrosis. - METHODS: For generating these instructions, a committee consisting of medical doctors and nursing staff providing care to cystic fibrosis patients, infectious diseases specialists and members of the department of infection control analyzed the patients' route through our cystic fibrosis unit during a routine clinic visit. First, the expert committee defined instructions concerning important infection control measures for each step. Next, each instruction was compared with the published literature and categorized as to its grade of evidence (I, II, 0). Instructions with grades of evidence I and II and instructions without demonstrated evidence (0) but theoretically reasonable and practically feasible, were accepted and outlined in a flow diagram. All other instructions were rejected. - RESULTS: The expert committee defined 45 instructions for infection control measures during an outpatient visit of a cystic fibrosis patient. 43 instructions within the categories "principles", "measures before entering the clinic", "measures in the examination room" and "measures when leaving the clinic" matched the criteria mentioned above and were accepted. 2 instructions were rejected. - CONCLUSIONS: Here we report evidence-based instructions for infection control in the setting of outpatient care for cystic fibrosis patients which are feasible in every day care. Since some instructions could only be assigned low evidence grade levels, i. e. II or 0, a further clarification of these issues by scientific investigations is warranted. Unresolved issues are primarily the recommendation for or against wearing a face mask for patients with certain pathogens and the issues of colonization with Stenotrophomonas maltophilia and Alcaligines xylosidans, but also with Aspergillus spp.. Continuous education of patients and healthcare workers as well as the validation of these practical instructions by a close monitoring and documentation of pathogens are of great importance.


Assuntos
Assistência Ambulatorial/métodos , Fibrose Cística/terapia , Pessoal de Saúde , Controle de Infecções/normas , Pacientes Ambulatoriais , Infecções Respiratórias/prevenção & controle , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/microbiologia , Humanos , Lactente , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Infecções Respiratórias/complicações , Infecções Respiratórias/transmissão
14.
Int J Oncol ; 24(1): 143-51, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14654951

RESUMO

The MDM2 proto-oncogene encodes a 90-kDa protein that binds to and inactivates the tumor suppressor p53. Several reports describe the presence of different alternatively, as well as, aberrantly spliced transcripts of the MDM2 mRNA in a variety of human cancers that have lost the ability to bind p53. Due to the transforming ability of at least some of the isoforms it has been suggested that they might contribute to tumorigenesis. Here we show that shorter MDM2 transcripts are also widely expressed in normal tissues, including lung and renal tissue, and in lymphocytes. Alteration in MDM2 RNA transcripts were found in the majority of the samples. Although we cannot exclude that alterations in MDM2 preferentially occur during cancer development, our data rather indicate that in this context the commonly observed transcript variants may also possess a normal physiological function.


Assuntos
Processamento Alternativo , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , Sequência de Bases , Western Blotting , Mama/metabolismo , Mucosa Gástrica/metabolismo , Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Rim/metabolismo , Linfócitos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Nucleares/metabolismo , Biossíntese de Proteínas , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2 , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/metabolismo , Transcrição Gênica/genética
15.
Int J Oncol ; 21(2): 243-9, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12118317

RESUMO

p53 suppressor gene mutations are a well known step which occurs in the late stages of the complex tumourigenesis of colorectal cancer. A deregulation of p53 protein function may be associated with increased neovascularization and aggressive tumour growth. In vitro studies have shown that these genetic alterations cause a loss of wild-type p53-induced anti-angiogenetic control and could possibly induce expression of the neoangiogenic vascular endothelial growth factor (VEGF). Therefore, this in vivo study was performed to assess p53 mutations, i.e. hot spots in exons 4-9, in primary colorectal cancers and in corresponding liver metastases in order to test whether there is an association between p53 mutated tumours with increased microvessel density (MVD) and VEGF overexpression. Twenty-two tissue samples taken from primary colorectal cancers and the corresponding liver metastases were immediately snap-frozen in liquid nitrogen and fixed in formaldehyde. After DNA extraction exons 4-9 were amplified and directly sequenced. Cryostat sections were stained immunohistochemically using antibodies against VEGF, CD34, and p53 protein. A modified semiquantitative Weidner score and interactive computerized image analysis was used to assess MVD. Overexpression of immunohistochemically detected p53 protein was found in 7 of the 11 primary tumours and liver metastases (64%). Sequencing showed 3 out of 11 primary tumours (27%) and 5 out of 11 liver metastases (46%) to have p53 point or frameshift mutations; these samples tested immunohistochemically positive for p53 protein. Two p53 mutations in samples of liver metastases were not detectable in the corresponding primaries. We detected one frameshift mutation in exon 4 that has not yet been described in the literature. Tumour samples with p53 mutations and increased VEGF immunoreactivity were associated with higher MVD (p<0.01 and p<0.05, respectively). However, there was no association detected immunohistochemically between p53 and MVD as well as p53 mutations and VEGF overexpression. Our data demonstrate specific genetic alterations in the coding regions of p53 suppressor gene in both primary colorectal cancers and corresponding liver metastases, these alterations are associated with an increase in MVD, but not in VEGF overexpression. In addition, a novel frameshift mutation in both colorectal cancer and metastasis is described.


Assuntos
Neoplasias Colorretais/genética , Mutação da Fase de Leitura , Neoplasias Hepáticas/genética , Neovascularização Patológica/patologia , Proteína Supressora de Tumor p53/genética , Antígenos CD34/metabolismo , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Primers do DNA/química , DNA de Neoplasias/análise , Fatores de Crescimento Endotelial/metabolismo , Éxons/genética , Feminino , Humanos , Técnicas Imunoenzimáticas , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/secundário , Linfocinas/metabolismo , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Reação em Cadeia da Polimerase , Prognóstico , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
16.
Oncol Rep ; 8(5): 1007-11, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11496306

RESUMO

We analysed the effects of caffeine and taxol on the radiobiological behaviour of two human sarcoma cell lines (RD, SK-LMS-1) each with a p53 missense mutation. Treatment with 2 mM caffeine resulted in an inhibition of the irradiation induced G2/M arrest in both cell lines. This effect was coupled with a radiosensitization in cell line SK-LMS-1 after an irradiation with 6 Gy (enhancement factor of 5.0). However, the effect of radiosensitization was not correlated with an induction of apoptosis. Incubation with 20 nM taxol increased the irradiation induced apoptosis almost 3-fold in cell line SK-LMS-1, but not in cell line RD. However, taxol had no effect on the irradiation induced G2/M arrest or radiosensitivity in either cell line. The results support the hypothesis that the prevention of irradiation induced G2/M arrest but not the induction of apoptosis plays a critical role in determining radiosensitivity in sarcoma cell lines with p53 mutations.


Assuntos
Apoptose/efeitos da radiação , Ciclo Celular/efeitos da radiação , Fase G2/efeitos da radiação , Genes p53/genética , Mitose/efeitos da radiação , Mutação de Sentido Incorreto , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Sarcoma/radioterapia , Células Tumorais Cultivadas/efeitos da radiação , Apoptose/efeitos dos fármacos , Cafeína/farmacologia , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Fase G2/efeitos dos fármacos , Humanos , Mitose/efeitos dos fármacos , Paclitaxel/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Sarcoma/tratamento farmacológico , Sarcoma/genética , Células Tumorais Cultivadas/efeitos dos fármacos
17.
Mutat Res ; 456(1-2): 39-44, 2000 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-11087894

RESUMO

The human MDM2 oncogene, well known as the tumor suppressor gene p53's partner, plays an important role in tumorigenesis whether it is dependent on or independent of TP53. In this study, we investigated in a PCR-sequencing analysis the exon 11 of the human MDM2 gene for gene alterations. A MboII polymorphism occurs in 8% of normal blood donors (8 out of 100 probands) and in 13% of the soft tissue sarcoma patients (11 out of 82 patients). Of note was that two STS patients carried the gene alteration only in the tumor specimens heterozygously but not in normal tissue. In a Kaplan-Meier analysis, patients without the polymorphism, indicated a median survival rate of 57 months, whereas, patients with the polymorphism survived on average only 38 months. We suggest that this polymorphism might be associated with an increased cancer susceptibility.


Assuntos
Proteínas Nucleares , Oncogenes , Polimorfismo de Fragmento de Restrição , Proteínas Proto-Oncogênicas/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Sequência de Bases , Doadores de Sangue , DNA/genética , Primers do DNA/genética , DNA de Neoplasias/genética , Desoxirribonucleases de Sítio Específico do Tipo II , Éxons , Genes p53 , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-mdm2
18.
Eur J Med Res ; 5(3): 110-4, 2000 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-10756164

RESUMO

UNLABELLED: Biliary atresia (BA) is one of the most frequent causes of neonatal cholestasis. Portoenterostomy is one therapeutic option in these patients with a success rate of 30-40%. To answer the question of therapy liver transplantation or Kasai operation - we analyzed 36 consecutive patients being followed in our center during the past 7 years. Two groups were formed: group I : patients developing cirrhosis within the first 2 years of life with the need for liver transplantation (n = 21). Group II: patients without need for transplantation within the first 2 years of life (n = 15). The two groups were compared regarding birth weight, age at diagnosis, age at Kasai-procedure, liver histology. The following biochemical parameters were analyzed at the time of diagnosis, 1 week and 5 weeks after Kasai: AST, ALT, gammaGT, and bilirubin. - RESULTS: Clinical characteristics were similar in both groups. However BA was diagnosed in group I 8.2 weeks after birth compared to 5.6 wk in group II. gammaGT, ALT, AST, and bilirubin were similar in both groups at the time of diagnosis and 1 wk after Kasai. However 5 wk after Kasai gammaGT was 276 U/l in group I compared to 72 U/l in group II (p <0.001), bilirubin was 6.3mg/dl in group I compared to 2. 3mg/dl in group II (p <0.001). - CONCLUSION: Kasai operation before the 7th wk of life increases the success rate of this technique significantly. Children with cirrhosis at the time of diagnosis should be evaluated for primary liver transplantation. gammaGT and bilirubin 5 weeks after Kasai operation may be useful markers for the success of this procedure. Patients with a gammaGT > 100 U/l and a bilirubin level >5mg/dl should be followed closely and should be evaluated for liver transplantation early.


Assuntos
Atresia Biliar/cirurgia , Transplante de Fígado , Portoenterostomia Hepática , Bilirrubina/sangue , Peso ao Nascer , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
19.
Oral Maxillofac Surg ; 16(2): 189-96, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22592457

RESUMO

INTRODUCTION: Hypoxia plays a major role in tumor progression, therapy resistance and for prognosis of oral squamous cell carcinoma (OSCC). The crucial step as a response to hypoxia is the activation and stabilization of the alpha subunit of hypoxia inducible factor 1 (HIF-1α). HIF-1: HIF-1 regulates the expression of different genes to adapt the tumor cells to reduced oxygenation. The HIF-1 system is intrinsic regulated by von Hippel-Lindau protein (pVHL). Main downstream proteins are the glucose transporter 1 (GLUT-1), carbonic anhydrase IX (CAIX), and vascular endothelial growth factor (VEGF). For therapeutical stratification in OSCC, it is important to understand the mechanism caused by hypoxic stress and to comprehend the resulting adaptive process in cancer cells. Therefore, an overview of HIF-1α-depending protein expression, focussed on the expression of GLUT-1, CAIX, and VEGF and their prognostic significance in OSCC is given. CONCLUSION: Several unique roles of hypoxic pathway in the context of tumor progression are described in this review. As a consequence, a marker panel is proposed to allow a more individualized prognosis in OSCC patients. This marker panel should include beside HIF-1α, pVHL, and GLUT-1.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Hipóxia Celular/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Antígenos de Neoplasias/genética , Anidrase Carbônica IX , Anidrases Carbônicas/genética , Carcinoma de Células Escamosas/mortalidade , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Transportador de Glucose Tipo 1/genética , Humanos , Mucosa Bucal/patologia , Neoplasias Bucais/mortalidade , Prognóstico , Estatística como Assunto , Taxa de Sobrevida , Fator A de Crescimento do Endotélio Vascular/genética
20.
Aliment Pharmacol Ther ; 36(3): 266-73, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22670841

RESUMO

BACKGROUND: The prevention and treatment of liver disease associated with cystic fibrosis remain a significant unresolved problem. AIM: To assess the long-term effects of continuous ursodeoxycholic acid (UDCA) therapy in cystic fibrosis patients with constantly elevated serum liver enzymes. METHODS: The primary endpoint was the incidence of overt liver disease. Between 1989 and 2005, UDCA treatment was started in 98 subjects from a cohort of 382 cystic fibrosis patients. These subjects were compared with a historic control group of 352 subjects who attended our centre between 1975 and 1989 before UDCA became standard treatment. For the long-term comparison of liver function and lung function tests, a group of 98 matched contemporary cystic fibrosis patients were compared with the 98 subjects treated with UDCA. RESULTS: Overt liver disease developed in only one of the 382 patients who was treated with UDCA for increased serum liver enzymes compared with nine patients in the historic control group (P < 0.05). Serum liver enzyme levels declined in most patients receiving UDCA treatment during the 17-year follow-up (87/98, P < 0.05). No difference was seen in lung function between subjects with cystic fibrosis-related liver disease and the matched controls. CONCLUSIONS: Regular and systematic screening for liver involvement enables early introduction of UDCA therapy in affected cystic fibrosis patients, reduces the development of severe liver disease and leads to a significant and persistent improvement in serum liver tests, without impairing long-term pulmonary outcome.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colagogos e Coleréticos/uso terapêutico , Fibrose Cística/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Colagogos e Coleréticos/efeitos adversos , Fibrose Cística/complicações , Feminino , Humanos , Lactente , Testes de Função Hepática , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Ácido Ursodesoxicólico/efeitos adversos , Adulto Jovem
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