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1.
Int J Mol Sci ; 18(10)2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-28937589

RESUMO

The development of cervical cancer is frequently accompanied by the integration of human papillomaviruses (HPV) DNA into the host genome. Viral-cellular junction sequences, which arise in consequence, are highly tumor specific. By using these fragments as markers for tumor cell origin, we examined cervical cancer clonality in the context of intra-tumor heterogeneity. Moreover, we assessed the potential of these fragments as molecular tumor markers and analyzed their suitability for the detection of circulating tumor DNA in sera of cervical cancer patients. For intra-tumor heterogeneity analyses tumors of 8 patients with up to 5 integration sites per tumor were included. Tumor islands were micro-dissected from cryosections of several tissue blocks representing different regions of the tumor. Each micro-dissected tumor area served as template for a single junction-specific PCR. For the detection of circulating tumor-DNA (ctDNA) junction-specific PCR-assays were applied to sera of 21 patients. Samples were collected preoperatively and during the course of disease. In 7 of 8 tumors the integration site(s) were shown to be homogenously distributed throughout different tumor regions. Only one tumor displayed intra-tumor heterogeneity. In 5 of 21 analyzed preoperative serum samples we specifically detected junction fragments. Junction-based detection of ctDNA was significantly associated with reduced recurrence-free survival. Our study provides evidence that HPV-DNA integration is as an early step in cervical carcinogenesis. Clonality with respect to HPV integration opens new perspectives for the application of viral-cellular junction sites as molecular biomarkers in a clinical setting such as disease monitoring.


Assuntos
Biomarcadores Tumorais/análise , DNA Tumoral Circulante/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Sistema Livre de Células , DNA Viral/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Células Tumorais Cultivadas
2.
Eur Arch Otorhinolaryngol ; 270(10): 2667-76, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23430080

RESUMO

Allergic rhinitis (AR), nasal polyps (NP) as well as chronic rhinosinusitis (CRS) are all known to be associated with eosinophilic infiltration and elevated numbers of mast cells (MC) within the mucosa. Both cell types and their markers eosinophilic cationic protein (ECP) and tryptase are utilized in the diagnosis and management of chronic sino-nasal diseases. Mucosal cytology samples were gathered by cytobrush, histological samples were obtained from the inferior turbinate. In both sample sets, the number of eosinophils and MC was determined. Their corresponding markers ECP and tryptase were quantified from nasal discharge. Patients were grouped with reference to their main diagnosis: AR (n = 34), NP (n = 25), CRS (n = 27) and controls (n = 34). Eosinophil counts from cytobrush and ECP levels were significantly elevated in NP compared to all other groups-31- and 13-fold over control, respectively. However, histologic review did not reveal any difference in eosinophil count among groups. Tryptase was significantly elevated threefold in AR versus CRS and controls. No correlation to cytological and histological MC counts could be found. ECP levels in nasal discharge as well as eosinophil counts can provide useful information with regard to the diagnosis. Likewise, tryptase concentrations can do. The presented data show that the measurement of markers in nasal discharge is superior in differentiating among diagnosis groups. Given that the collection of nasal secretions is more comfortable for patients than the more invasive techniques, we recommend first line ECP and tryptase testing performed on nasal secretions.


Assuntos
Eosinófilos/citologia , Mastócitos/citologia , Muco/citologia , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Rinite Alérgica Perene/patologia , Rinite/patologia , Sinusite/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Estudos de Casos e Controles , Doença Crônica , Proteína Catiônica de Eosinófilo/metabolismo , Eosinófilos/metabolismo , Feminino , Humanos , Masculino , Mastócitos/metabolismo , Pessoa de Meia-Idade , Muco/metabolismo , Mucosa Nasal/citologia , Mucosa Nasal/metabolismo , Pólipos Nasais/metabolismo , Rinite/metabolismo , Rinite Alérgica , Rinite Alérgica Perene/metabolismo , Sinusite/metabolismo , Triptases/metabolismo , Conchas Nasais/citologia , Conchas Nasais/metabolismo , Conchas Nasais/patologia , Adulto Jovem
3.
Arch Argent Pediatr ; 121(6): e202303017, 2023 12 01.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-37471470

RESUMO

Introduction. Segmental overgrowth syndromes are a group of rare diseases characterized by overgrowth in one or more parts of the body, mostly related to mosaic mutations in the AKT/PI3K/mTOR and RAS- MAPK signaling pathway. Our objective was to analyze the clinical and auxological characteristics and health-related quality of life (HRQoL) in this group of patients at a tertiary care hospital. Population and methods. Cross-sectional study of a follow-up cohort. Age, sex, sociodemographic data, anthropometric measurements of the affected and contralateral segments, complications, treatment, quality of life (PedsQL 4.0), and pain were analyzed. Central and dispersion measures were estimated. A univariate analysis between the quality of life and study variables was done. Results. A total of 50 patients were included; 29 were males. Median age: 9.95 (r: 1.44-17.81) years. The most common diagnosis was PIK3CA-related overgrowth spectrum (PROS) (37/50). The median number of affected segments was 2 (r: 1-7) per patient. Vascular malformations were observed in 40, and capillary malformations, in 20 patients. Pain was the most common complication (24/50). An asymmetry of the lower extremities of < 5 cm was observed in 31 patients. In most children, height was between the 50th and 97th percentiles. A lower HRQoL was observed among girls, patients with complex vascular malformations, and those with unmet basic needs (UBNs). Conclusions. PROS was the most common diagnosis. Pain was the most common complication. HRQoL was lower among girls, patients with combined vascular malformations, and those with UBNs.


Introducción. Los síndromes de sobrecrecimiento corporal segmentario son un grupo de enfermedades poco frecuentes caracterizadas por exceso de crecimiento en una o más partes del cuerpo relacionadas, en su mayoría, con mutaciones en mosaico en la vía de señalización AKT/PI3K/mTOR y RAS-MAPK. Nuestro objetivo fue analizar las características clínicas y auxológicas, y la calidad de vida relacionada a salud (CVRS) en este grupo de pacientes en un hospital de tercer nivel de atención. Población y métodos. Estudio transversal de una cohorte en seguimiento. Se analizaron edad, sexo, datos sociodemográficos, mediciones antropométricas del segmento afectado y del contralateral, complicaciones, tratamiento, calidad de vida (PedsQL4.0) y dolor. Se calcularon medidas centrales y de dispersión. Se realizó análisis univariado entre calidad de vida y variables incluidas. Resultados. Se incluyeron 50 pacientes, 29 varones. Mediana de edad 9,95 (r 1,44-17,81) años. El diagnóstico más frecuente fue síndrome de sobrecrecimiento relacionado a PIK3CA (PROS) (37/50). Mediana de número de segmentos afectados 2 (r: 1-7) por niño. Cuarenta casos presentaron malformación vascular; 20, capilar. El dolor (24/50) fue la complicación más frecuente. Treinta y un pacientes mostraron asimetría de longitud de miembros inferiores, < 5 cm. La estatura se ubicó entre los centilos 50 y 97 en la mayoría de los niños. Menor CVRS se observó en mujeres, en pacientes con malformación vascular compleja y necesidades básicas insatisfechas (NBI). Conclusiones. PROS fue el diagnóstico más frecuente. El dolor fue una complicación frecuente. La CVRS fue menor en mujeres, pacientes con malformación vascular combinada y NBI.


Assuntos
Qualidade de Vida , Malformações Vasculares , Masculino , Feminino , Humanos , Criança , Adolescente , Estudos Transversais , Transdução de Sinais , Mutação , Síndrome , Dor
4.
BMJ Open ; 12(11): e064277, 2022 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-36410815

RESUMO

OBJECTIVES: The aim of this study was to describe the practice variation in dispensation of secondary stroke preventive drugs among patients at different primary care centres (PCCs) in Stockholm region and to identify factors that may explain the variation. DESIGN: Cohort study using administrative data from the Stockholm region. SETTING: Stockholm Health Care Region, Sweden, serving a population of 2.3 million inhabitants, hospital and PCC data. PARTICIPANTS: All patients (n=9761) with ischaemic stroke treated in hospital from 1 July 2009 to 30 June 2014 were included. Of these, 7562 patients registered with 187 PCCs were analysed. Exclusion criteria were; deceased patients, age <18, haemorrhagic stroke and/or switching PCC. PRIMARY AND SECONDARY OUTCOME MEASURES: As primary outcome the impact of PCC organisation variables and patient characteristics on the dispensation of statins, antiplatelets, antihypertensives and anticoagulants were analysed. Secondarily, the unadjusted practice variation of preventive drug dispensation of 187 PCCs is described. RESULTS: There was up to fourfold practice variation in dispensation of all secondary preventive drugs. Factors associated with a lower level of dispensed statins were privately run PCCs (OR 0.91 (95% CI 0.82 to 1.00)) and the patient being woman. Increased statin use was associated with a higher number of specialists in family medicine (OR 1.03 (95% CI 1.01 to 1.05)) and a higher proportion of patients registered with a specific physician (OR 1.37 (95% CI 1.11 to 1.68)). Women had on average a lower number of dispensed antihypertensives. CONCLUSIONS: A high practice variation for dispensation of all secondary preventive drugs was observed. Patient and PCC level factors indicating good continuity of care and high level of general practitioner education were associated with higher use of statins. Findings are of importance to policymakers as well as individual providers of care, and more research and actions are needed to minimise inequality in healthcare.


Assuntos
Isquemia Encefálica , Clínicos Gerais , Inibidores de Hidroximetilglutaril-CoA Redutases , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Feminino , Acidente Vascular Cerebral/prevenção & controle , Estudos de Coortes , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Atenção Primária à Saúde
5.
Strahlenther Onkol ; 186(7): 374-81, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20582393

RESUMO

BACKGROUND AND PURPOSE: For definitive radiochemotherapy, 5-fluorouracil/cisplatin protocols have been considered the standard of care for esophageal carcinoma over the last 2 decades. By contrast, most patients treated at the University Hospital, LMU Munich, Germany, received 5-fluorouracil/mitomycin C. The objective of this retrospective analysis was to determine the value of 5-fluorouracil/mitomycin-C-based therapy. PATIENTS AND METHODS: Tumor stage, treatment received, and outcome data of patients treated for esophageal cancer between 1982 and 2007 were collected; endpoint of the analysis was overall survival. RESULTS: 298 patients with inoperable cancer of the esophagus were identified (16.8% adenocarcinoma, 77.5% squamous cell carcinoma). At diagnosis, 61.7% (184/298) had UICC stage III-IV, 54.4% (162/298) positive lymph nodes, and 26.5% (79/298) metastatic disease. 74.5% of all patients (222/298) received radiation doses between 55 and 65 Gy, 65.8% (196/298) were subjected to concomitant chemotherapy. The median follow-up period (patients alive) was 4.1 years. A significant increase of overall survival (p < 0.0001) in the radiochemotherapy versus the radiotherapy-alone group was observed. 52% (102/196) in the 5-fluorouracil/ mitomycin C group had tumor stages comparable to the RTOG 85-01 study cohort (T1-3 N0-1 M0). The median survival in this subgroup was 18.2 months, 3- and 5-year survival rates were 22.7% (21/102) and 15.0% (13/102), respectively. CONCLUSION: Despite being nominally inferior to platinum-based radiochemotherapy, the overall survival rates are in a similar range. Thus, the mitomycin-C-based radiochemotherapy approach may considered to be as effective as the standard therapy. However, there is no randomized trial available in order to prove the equality.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Terapia Combinada , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Mitomicina/efeitos adversos , Estadiamento de Neoplasias , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Sistema de Registros , Estudos Retrospectivos , Análise de Sobrevida
6.
Praxis (Bern 1994) ; 108(14): 923-930, 2019.
Artigo em Alemão | MEDLINE | ID: mdl-31662109

RESUMO

Integrated Complex Treatment for Extreme Anorexia Nervosa; An Interdisciplinary Treatment Concept of the University Hospital Zurich Abstract. The serious physical mental and psychosocial morbidity due to anorexia nervosa is often perceived by sufferers as less serious than from their environment. Doctors and other healthcare professionals are therefore confronted with the difficulty that urgent medical treatment is considered as unnecessary or even threatening by those affected. Although patients with anorexia nervosa usually wish to improve their condition, they are usually only able to tolerate treatment aimed at normalizing eating behavior and gaining weight in response to high external pressure. In view of this situation, an interdisciplinary team with experience in these treatments is required to treat these patients. Close cooperation is necessary to ensure a supporting treatment framework.


Assuntos
Anorexia Nervosa , Anorexia Nervosa/terapia , Terapia Combinada , Hospitais Universitários , Humanos , Pacientes Internados , Aumento de Peso
7.
Mol Cell Biol ; 25(5): 1577-85, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15713618

RESUMO

The RNA-processing exosome is a complex of riboexonucleases required for 3'-end formation of some noncoding RNAs and for the degradation of mRNAs in eukaryotes. The nuclear form of the exosome functions in an mRNA surveillance pathway that retains and degrades improperly processed precursor mRNAs within the nucleus. We report here that the nuclear exosome controls the level of NAB2 mRNA, encoding the nuclear poly(A)+-RNA-binding protein Nab2p. Mutations affecting the activity of the nuclear, but not the cytoplasmic, exosome cause an increase in the amount of NAB2 mRNA. Cis- and trans-acting mutations that inhibit degradation by the nuclear-exosome subunit Rrp6p result in elevated levels of NAB2 mRNA. Control of NAB2 mRNA levels occurs posttranscriptionally and requires a sequence of 26 consecutive adenosines (A26) in the NAB2 3' untranslated region, which represses NAB2 3'-end formation and sensitizes the transcript to degradation by Rrp6p. Analysis of NAB2 mRNA levels in a nab2-1 mutant and in the presence of excess Nab2p indicates that Nab2p activity negatively controls NAB2 mRNA levels in an A26- and Rrp6p-dependent manner. These findings suggest a novel regulatory circuit in which the nuclear exosome controls the level of NAB2 mRNA in response to changes in the activity of Nab2 protein.


Assuntos
Exorribonucleases/fisiologia , Regulação Fúngica da Expressão Gênica , Proteínas de Transporte Nucleocitoplasmático/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/fisiologia , Regiões 3' não Traduzidas/genética , Regiões 3' não Traduzidas/metabolismo , Sequência de Bases , Núcleo Celular/metabolismo , Exorribonucleases/genética , Complexo Multienzimático de Ribonucleases do Exossomo , Expressão Gênica/genética , Dados de Sequência Molecular , Mutação/genética , Proteínas de Transporte Nucleocitoplasmático/fisiologia , Poli A/genética , Poli A/metabolismo , Proteínas de Ligação a Poli(A)/metabolismo , Estabilidade de RNA , RNA Fúngico/metabolismo , Proteínas de Ligação a RNA/fisiologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/fisiologia
8.
Arch. argent. pediatr ; 121(6): e202303017, dic. 2023. tab, graf
Artigo em Inglês, Espanhol | LILACS, BINACIS | ID: biblio-1517881

RESUMO

Introducción. Los síndromes de sobrecrecimiento corporal segmentario son un grupo de enfermedades poco frecuentes caracterizadas por exceso de crecimiento en una o más partes del cuerpo relacionadas, en su mayoría, con mutaciones en mosaico en la vía de señalización AKT/PI3K/mTOR y RAS-MAPK. Nuestro objetivo fue analizar las características clínicas y auxológicas, y la calidad de vida relacionada a salud (CVRS) en este grupo de pacientes en un hospital de tercer nivel de atención. Población y métodos. Estudio transversal de una cohorte en seguimiento. Se analizaron edad, sexo, datos sociodemográficos, mediciones antropométricas del segmento afectado y del contralateral, complicaciones, tratamiento, calidad de vida (PedsQL4.0) y dolor. Se calcularon medidas centrales y de dispersión. Se realizó análisis univariado entre calidad de vida y variables incluidas. Resultados. Se incluyeron 50 pacientes, 29 varones. Mediana de edad 9,95 (r 1,44-17,81) años. El diagnóstico más frecuente fue síndrome de sobrecrecimiento relacionado a PIK3CA (PROS) (37/50). Mediana de número de segmentos afectados 2 (r: 1-7) por niño. Cuarenta casos presentaron malformación vascular; 20, capilar. El dolor (24/50) fue la complicación más frecuente. Treinta y un pacientes mostraron asimetría de longitud de miembros inferiores, < 5 cm. La estatura se ubicó entre los centilos 50 y 97 en la mayoría de los niños. Menor CVRS se observó en mujeres, en pacientes con malformación vascular compleja y necesidades básicas insatisfechas (NBI). Conclusiones. PROS fue el diagnóstico más frecuente. El dolor fue una complicación frecuente. La CVRS fue menor en mujeres, pacientes con malformación vascular combinada y NBI.


Introduction. Segmental overgrowth syndromes are a group of rare diseases characterized by overgrowth in one or more parts of the body, mostly related to mosaic mutations in the AKT/PI3K/mTOR and RASMAPK signaling pathway. Our objective was to analyze the clinical and auxological characteristics and health-related quality of life (HRQoL) in this group of patients at a tertiary care hospital. Population and methods. Cross-sectional study of a follow-up cohort. Age, sex, sociodemographic data, anthropometric measurements of the affected and contralateral segments, complications, treatment, quality of life (PedsQL 4.0), and pain were analyzed. Central and dispersion measures were estimated. A univariate analysis between the quality of life and study variables was done. Results. A total of 50 patients were included; 29 were males. Median age: 9.95 (r: 1.44­17.81) years. The most common diagnosis was PIK3CA-related overgrowth spectrum (PROS) (37/50). The median number of affected segments was 2 (r: 1­7) per patient. Vascular malformations were observed in 40, and capillary malformations, in 20 patients. Pain was the most common complication (24/50). An asymmetry of the lower extremities of < 5 cm was observed in 31 patients. In most children, height was between the 50th and 97th percentiles. A lower HRQoL was observed among girls, patients with complex vascular malformations, and those with unmet basic needs (UBNs). Conclusions. PROS was the most common diagnosis. Pain was the most common complication. HRQoL was lower among girls, patients with combined vascular malformations, and those with UBNs.


Assuntos
Humanos , Pré-Escolar , Criança , Adolescente , Qualidade de Vida , Malformações Vasculares , Dor , Síndrome , Transdução de Sinais , Estudos Transversais , Mutação
9.
Front Microbiol ; 8: 444, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28373866

RESUMO

The organohalide-respiring Epsilonproteobacterium Sulfurospirillum multivorans is able to grow with hydrogen as electron donor and with tetrachloroethene (PCE) as electron acceptor; PCE is reductively dechlorinated to cis-1,2-dichloroethene. Recently, a genomic survey revealed the presence of four gene clusters encoding NiFe hydrogenases in its genome, one of which is presumably periplasmic and membrane-bound (MBH), whereas the remaining three are cytoplasmic. To explore the role and regulation of the four hydrogenases, quantitative real-time PCR and biochemical studies were performed with S. multivorans cells grown under different growth conditions. The large subunit genes of the MBH and of a cytoplasmic group 4 hydrogenase, which is assumed to be membrane-associated, show high transcript levels under nearly all growth conditions tested, pointing toward a constitutive expression in S. multivorans. The gene transcripts encoding the large subunits of the other two hydrogenases were either not detected at all or only present at very low amounts. The presence of MBH under all growth conditions tested, even with oxygen as electron acceptor under microoxic conditions, indicates that MBH gene transcription is not regulated in contrast to other facultative hydrogen-oxidizing bacteria. The MBH showed quinone-reactivity and a characteristic UV/VIS spectrum implying a cytochrome b as membrane-integral subunit. Cell extracts of S. multivorans were subjected to native polyacrylamide gel electrophoresis (PAGE) and hydrogen oxidizing activity was tested by native staining. Only one band was detected at about 270 kDa in the particulate fraction of the extracts, indicating that there is only one hydrogen-oxidizing enzyme present in S. multivorans. An enrichment of this enzyme and SDS PAGE revealed a subunit composition corresponding to that of the MBH. From these findings we conclude that the MBH is the electron-donating enzyme system in the PCE respiratory chain. The roles for the other three hydrogenases remain unproven. The group 4 hydrogenase might be involved in hydrogen production upon fermentative growth.

11.
Cardiovasc Res ; 105(1): 96-106, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25377726

RESUMO

AIMS: Hypercholesterolaemia is a major risk factor for cardiovascular diseases and has been shown to influence angiogenesis in the hind limb ischaemia (HLI) model. The impaired up-regulation of angiogenic factors seems to be one of the underlying mechanisms for reduced vessel formation. Since we found that secretoneurin (SN) is up-regulated in hypoxic skeletal muscle cells and exerts beneficial effects in myocardial and HLI, we hypothesized that SN therapy might improve neovascularization in hypercholesterolaemic Apo E(-/-) (Apo E knockout) mice suffering from an impaired vascular response. METHODS AND RESULTS: For in vitro experiments, endothelial cells (ECs) were incubated with oxidized low-density lipoprotein (oxLDL) to mimic hypercholesterolaemia. EC function was impaired by oxLDL, but SN induced EC proliferation and in vitro tube formation under these conditions. In the HLI model, injection of SN plasmid resulted in a significant better outcome regarding blood flow recovery, amputation rate, and vessel density. In the myocardial infarction (MI) model, the SN group showed improvement in cardiac parameters. Aortic plaque area was not influenced by local SN injection. Interestingly, SN-induced recruitment of angiogenic monocytic cells was abolished under hypercholesterolaemia. CONCLUSIONS: SN gene therapy exerts beneficial effects in cardiovascular animal models in Apo E(-/-) mice without influencing atherosclerosis and might qualify as a promising therapy for cardiovascular disorders.


Assuntos
Apolipoproteínas E/deficiência , Terapia Genética , Isquemia/terapia , Isquemia Miocárdica/terapia , Neuropeptídeos/genética , Neuropeptídeos/uso terapêutico , Secretogranina II/genética , Secretogranina II/uso terapêutico , Animais , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/fisiopatologia , Aterosclerose/terapia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Membro Posterior/irrigação sanguínea , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/fisiopatologia , Hipercolesterolemia/terapia , Isquemia/genética , Isquemia/fisiopatologia , Lipoproteínas LDL/administração & dosagem , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Cardiovasculares , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Isquemia Miocárdica/genética , Isquemia Miocárdica/fisiopatologia , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Neuropeptídeos/fisiologia , Secretogranina II/fisiologia
12.
Praxis (Bern 1994) ; 108(6): 380, 2019 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-31039705
13.
Radiat Oncol ; 7: 60, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22501022

RESUMO

BACKGROUND AND OBJECTIVES: Treatment options for oesophageal cancer have changed considerably over the last decades with the introduction of multimodal treatment concepts dominating the progress in the field. However, it remains unclear in how far the documented scientific progress influenced and changed the daily routine practice. Since most patients with oesophageal cancer generally suffer from reduced overall health conditions it is uncertain how high the proportion of aggressive treatments is and whether outcomes are improved substantially. In order to gain insight into this we performed a retrospective analysis of patients treated at a larger tertiary referral centre over time course of 25 years. PATIENTS AND METHODS: Data of all patients diagnosed with squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the oesophagus, treated between 1983 and 2007 in the department of radiation oncology of the LMU, were obtained. The primary endpoint of the data collection was overall survival (calculated from the date of diagnosis until death or last follow up). Changes in basic clinical characteristics, treatment approach and the effect on survival were analysed after dividing the cohort into five subsequent time periods (I-V) with 5 years each. In a second analysis any pattern of change regarding the use of radio(chemo)therapy (R(C)T) with and without surgery was determined. RESULTS: In total, 503 patients with SCC (78.5%) and AC (18.9%) of the oesophagus were identified. The average age was 60 years (range 35-91 years). 56.5% of the patients were diagnose with advanced UICC stages III-IV. R(C)T was applied to 353 (70.2%) patients; R(C)T+ surgery was performed in 134 (26.6%) patients, 63.8% of all received chemotherapy (platinum-based 5.8%, 5-fluorouracil (5-FU)12.1%, 42.3% 5-FU and mitomycin C (MMC)). The median follow-up period was 4.3 years. The median overall survival was 21.4 months. Over the time, patients were older, the formal tumour stage was more advanced, the incidence of AC was higher and the intensified treatment had a higher prevalence. However there was only a trend for an improved OS over the years with no difference between RCT with or without surgery (p = 0.09). The use of radiation doses over 54 Gy and the addition of chemotherapy (p = 0.002) were associated with improved OS. CONCLUSION: Although more complex treatment protocols were introduced into clinical routine, only a minor progress in OS rates was detectable. Main predictors of outcome in this cohort was the addition of chemotherapy. The addition of surgery to radio-chemotherapy may only be of value for very limited patient groups.


Assuntos
Neoplasias Esofágicas/terapia , Adenocarcinoma/epidemiologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/estatística & dados numéricos , Quimiorradioterapia/tendências , Quimioterapia Adjuvante/estatística & dados numéricos , Quimioterapia Adjuvante/tendências , Terapia Combinada/tendências , Neoplasias Esofágicas/epidemiologia , Esofagectomia/estatística & dados numéricos , Esofagectomia/tendências , Feminino , Seguimentos , Alemanha/epidemiologia , Departamentos Hospitalares/estatística & dados numéricos , Hospitais Universitários/estatística & dados numéricos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Compostos Organoplatínicos/administração & dosagem , Radioterapia (Especialidade)/estatística & dados numéricos , Radioterapia Adjuvante/estatística & dados numéricos , Radioterapia Adjuvante/tendências , Estudos Retrospectivos , Resultado do Tratamento
14.
Fertil Steril ; 95(1): 338-41, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20850729

RESUMO

Expression of the pluripotency factors SOX-2, OCT-4, KLF-4, and NANOG was analyzed by quantitative real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence microscopy in the endometrium, myometrium, and endometriotic tissue of 36 patients. Aberrant expression of SOX-2 may indicate a stem cell origin of endometriosis, whereas the presence of all progenitor markers in endometrial tissue marks the endometrium as a potential source for induced pluripotent stem cell generation.


Assuntos
Biomarcadores/metabolismo , Endometriose , Endométrio/fisiologia , Células-Tronco Pluripotentes/fisiologia , Fatores de Transcrição SOXB1/genética , Adulto , Endometriose/genética , Endometriose/metabolismo , Endometriose/patologia , Endométrio/patologia , Feminino , Expressão Gênica/fisiologia , Proteínas de Homeodomínio/genética , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Pessoa de Meia-Idade , Proteína Homeobox Nanog , Fator 3 de Transcrição de Octâmero/genética , Células-Tronco Pluripotentes/citologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOXB1/metabolismo , Nicho de Células-Tronco/patologia , Nicho de Células-Tronco/fisiologia , Células Estromais/citologia , Células Estromais/fisiologia
15.
Radiat Oncol ; 6: 55, 2011 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-21615894

RESUMO

Since the 1980s major advances in surgery, radiotherapy and chemotherapy have established multimodal approaches as curative treatment options for oesophageal cancer. In addition the introduction of functional imaging modalities such as PET-CT created new opportunities for a more adequate patient selection and therapy response assessment.The majority of oesophageal carcinomas are represented by two histologies: squamous cell carcinoma and adenocarcinoma. In recent years an epidemiological shift towards the latter was observed. From a surgical point of view, adenocarcinomas, which are usually located in the distal third of the oesophagus, may be treated with a transhiatal resection, whereas squamous cell carcinomas, which are typically found in the middle and the upper third, require a transthoracic approach. Since overall survival after surgery alone is poor, multimodality approaches have been developed. At least for patients with locally advanced tumors, surgery alone can no longer be advocated as routine treatment. Nowadays, scientific interest is focused on tumor response to induction radiochemotherapy. A neoadjuvant approach includes the early and accurate assessment of clinical response, optimally performed by repeated PET-CT imaging and endoscopic ultrasound, which may permit early adaption of the therapeutic concept. Patients with SCC that show clinical response by PET CT are considered to have a better prognosis, regardless of whether surgery will be performed or not. In non-responding patients salvage surgery improves survival, especially if complete resection is achieved.


Assuntos
Carcinoma/terapia , Neoplasias Esofágicas/terapia , Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Humanos , Oncologia/métodos , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Radioterapia Adjuvante , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
16.
Expert Opin Drug Metab Toxicol ; 5(1): 57-69, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19236229

RESUMO

BACKGROUND: Piperacillin-tazobactam (PIP/TAZO) has been extensively used in adults with nosocomial infections and with fever and neutropenia. The available data considering the use of PIP/TAZO have not been reviewed in detail. OBJECTIVE: Review discussing the use of PIP/TAZO in neonatal and paediatric patients. METHODS: Medline search focusing on articles published in English. Owing to the paucity of randomized controlled trails, uncontrolled studies and case series were included. RESULTS/CONCLUSION: PIP/TAZO may safely be used in paediatric patients as an empiric treatment for serious infections in hospital environments where resistance to common first-line antimicrobials has emerged. The most common indications in paediatric patients are nosocomial infections owing to resistant Gram-negatives, exacerbation of pulmonary colonization with Psuedomonas aeruginosa in patients with cystic fibrosis, intra-abdominal infections, fever and neutropenia in paediatric cancer patients. The influence of PIP/TAZO routine use on the selection of extended-spectrum beta-lactamase producing Gram-negatives and on the prevalence of vancomycin-resistant enterococci is still a matter of debate. In particular the use of PIP/TAZO in neonates and PIP/TAZO monotherapy in paediatric cancer patients with fever and neutropenia should be investigated in prospective randomized studies including a sufficient number of patients.


Assuntos
Infecção Hospitalar/tratamento farmacológico , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Infecção Hospitalar/prevenção & controle , Humanos , Recém-Nascido , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/efeitos adversos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/uso terapêutico , Piperacilina/administração & dosagem , Piperacilina/efeitos adversos , Piperacilina/uso terapêutico , Combinação Piperacilina e Tazobactam
17.
J Immunother ; 27(2): 156-60, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14770087

RESUMO

Immunocompetent alloreactive donor lymphocytes directed against minor histocompatibility antigens are supposed to be responsible for graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) activity after allogeneic stem cell transplantation. The authors describe the detection of HA-1-specific T cells by peptide-loaded dimers and flow cytometry in the peripheral blood of a patient in complete remission but without GvHD after donor lymphocyte infusion for chemotherapy-resistant Philadelphia chromosome-positive acute lymphoblastic leukemia. The HA-1-specific T cells were sorted and an alloreactive, polyclonal T-cell line with specific lytic activity against HA-1-positive target cells, including leukemic cells, was established. Although P190 bcr/abl peptide-specific CD8positive T cells were detected in the peripheral blood at the same time, these T cells could not be expanded. Furthermore, no P190 bcr/abl peptide-specific T-cell response could be induced in vitro, even when peptide-loaded dendritic cells were used as stimulator cells. The authors conclude that in the absence of GvHD, HA-1-specific rather than P190 bcr/abl-specific T cells are responsible for ongoing GvL activity.


Assuntos
Linhagem da Célula , Transplante de Células , Efeito Enxerto vs Leucemia , Antígenos HLA-A/química , Células-Tronco Hematopoéticas/citologia , Imunoterapia/métodos , Leucemia/terapia , Linfócitos/citologia , Antígenos de Histocompatibilidade Menor/imunologia , Divisão Celular , Células Dendríticas/citologia , Dimerização , Citometria de Fluxo , Antígeno HLA-A2 , Humanos , Oligopeptídeos , Peptídeos/química , Fenótipo , Ligação Proteica , Linfócitos T/metabolismo
18.
Cell ; 116(1): 121-37, 2004 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-14718172

RESUMO

Modern medicine faces the challenge of developing safer and more effective therapies to treat human diseases. Many drugs currently in use were discovered without knowledge of their underlying molecular mechanisms. Understanding their biological targets and modes of action will be essential to design improved second-generation compounds. Here, we describe the use of a genome-wide pool of tagged heterozygotes to assess the cellular effects of 78 compounds in Saccharomyces cerevisiae. Specifically, lanosterol synthase in the sterol biosynthetic pathway was identified as a target of the antianginal drug molsidomine, which may explain its cholesterol-lowering effects. Further, the rRNA processing exosome was identified as a potential target of the cell growth inhibitor 5-fluorouracil. This genome-wide screen validated previously characterized targets or helped identify potentially new modes of action for over half of the compounds tested, providing proof of this principle for analyzing the modes of action of clinically relevant compounds.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Genoma Fúngico , Heterozigoto , Saccharomyces cerevisiae/efeitos dos fármacos , Fluoruracila/farmacologia , Perfilação da Expressão Gênica/métodos , Transferases Intramoleculares/efeitos dos fármacos , Transferases Intramoleculares/metabolismo , Molsidomina/farmacologia , Valor Preditivo dos Testes , RNA Ribossômico/efeitos dos fármacos , RNA Ribossômico/metabolismo , Reprodutibilidade dos Testes , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
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