RESUMO
BACKGROUND: Molecular informed therapy changed treatment patterns of metastatic colorectal cancer (mCRC). Recently KRAS G12, the most prevalent RAS mutation in mCRC, was investigated to be a negative predictive marker for the efficacy of trifluridine/tipiracil (FTD/TPI). Whether this proposed selectivity remains when FTD/TPI is combined with bevacizumab remains elusive. We aimed to describe the efficacy of FTD/TPI + bevacizumab depending on the RAS mutational status in a real-world population. PATIENTS AND METHODS: Patients from five different cancer centers in Austria who received FTD/TPI + bevacizumab in any treatment line having available information on their molecular profile were eligible. Data were retrospectively collected by chart review. Survival data were compared using log-rank test. Multivariate Cox regression models included several established covariates. RESULTS: One hundred and twenty-three patients with mCRC were included in this study. Median overall survival (OS) was highly similar in the RAS wild type (WT) [9.63 months (95% confidence interval [CI] 8.055-13.775 months)] and the RAS mutant cohorts [8.78 months (95% CI 8.055-11.014 months)], which was confirmed in a multivariable model adjusting for potential confounders; hazard ratio (HR): 1.05 (95% CI 0.618-1.785; P = 0.857). In addition, no effect of KRAS G12 status on patient outcome was observed. In detail, OS was 8.88 months (95% CI 7.332-12.921 months) in patients with KRAS G12 mutation, compared to 9.47 months (95% CI 8.088-11.375 months) in patients with RAS WT/no-KRAS G12 disease [HR: 0.822 (95% CI 0.527-1.282; P = 0.387)]. CONCLUSION: This real-world study indicates that the efficacy of FTD/TPI + bevacizumab is independent of RAS mutational status and that bevacizumab may therefore mitigate the potentially limited efficacy of FTD/TPI monotherapy in the KRAS G12-mutated population.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Demência Frontotemporal , Humanos , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Uracila , Estudos Retrospectivos , Trifluridina/farmacologia , Trifluridina/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
BACKGROUND: Metastatic patterns have been linked with prognosis in colorectal cancer. We aim to determine the distribution of metastases, their dynamics during disease and their prognostic impact for specific clinical treatment scenarios (resection of metastasis and/or systemic treatment, best supportive care). MATERIAL AND METHODS: 978 patients diagnosed with metastatic colorectal adenocarcinoma treated at three oncological centers from 2006 to 2018 were included. Overall survival was assessed depending on tumor load, distribution of metastases and treatment of the patients. RESULTS: Most patients had single site metastasis (n = 684; 69.9%): 398 patients had liver (n = 398; 40.7%) and 103 patients had lung only metastasis (10.6%). The number of organs involved in metastases at diagnosis was highly prognostic (HR 0.77; CI 0.65, 0.90), whereas the additional gain of metastases during progression of the disease was not. The majority of patients (62.9-74.2%) with initial lung, liver or both metastases retained their initial metastatic status. In the overall population, lung only metastases were associated with the most favorable outcome (HR 0.64; CI 0.50, 0.81). This was also observed in patients receiving best supportive care (HR 0.45; CI 0.27, 0.75). Resection of lung only metastases resulted in longer median survival (102.2 months). A relevant survival difference in patients treated by systemic therapy alone was not observed. Lung only metastasis was associated with rectal cancer (p < .001) and RAS-mutation (p = .01); both, lung and liver metastasis were associated with time from diagnosis to first metastasis (p < .001). CONCLUSION: The number of organs involved in metastasis at diagnosis but not the total cumulative number of involved organs is of prognostic relevance in colorectal adenocarcinoma. This prognostic relevant initial metastasis distribution remains unchanged in the majority of patients during the disease. However, the prognostic impact of the metastatic pattern is potentially altered by treatment modality.
Assuntos
Adenocarcinoma , Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Pulmonares , Adenocarcinoma/terapia , Neoplasias Colorretais/terapia , Humanos , Neoplasias Pulmonares/terapia , Prognóstico , Estudos RetrospectivosRESUMO
Hematopoietic macrochimerism, which is rarely seen after orthotopic liver transplantation (OLT), has been linked to the development of graft versus host disease (GvHD). We report on a patient with GvHD after OLT in whom full engraftment of donor-derived, multilineage hematopoiesis occurred, indicating that the liver contains pluripotent hematopoietic progenitor cells (HPC) capable to restore hematopoiesis in recipients. Although preventing graft rejection, standard immunosuppressive therapy may be under certain immunological conditions not sufficient to prevent GvHD. Age-, disease-, and treatment-related variables might be critical determinants for the development of an effective alloreactive T-cell response leading to the establishment of full hematopoietic chimerism.
Assuntos
Hematopoese , Transplante de Fígado , Doadores de Tecidos , Idoso , Linhagem da Célula , Humanos , MasculinoRESUMO
Because of its semi-solid character in dissemination and growth, advanced ovarian cancer with its hundreds of peritoneal tumor nodules and plaques appears to be an excellent in vivo model for studying the cancer stem cell hypothesis. The most important obstacle, however, is to adequately define and isolate these tumor-initiating cells endowed with the properties of anoikis-resistance and unlimited self-renewal. Until now, no universal single marker or marker constellation has been found to faithfully isolate (ovarian) cancer stem cells. As these multipotent cells are known to possess highly elaborated efflux systems for cytotoxic agents, these pump systems have been exploited to outline putative stem cells as a side-population (SP) via dye exclusion analysis. Furthermore, the cells in question have been isolated via flow cytometry on the basis of cell surface markers thought to be characteristic for stem cells.In the Vienna variant of the ovarian cancer cell line A2780 a proof-of-principle model with both a stable SP and a stable ALDH1A1+ cell population was established. Double staining clearly revealed that both cell fractions were not identical. Of note, A2780V cells were negative for expression of surface markers CD44 and CD117 (c-kit). When cultured on monolayers of healthy human mesothelial cells, green-fluorescence-protein (GFP)-transfected SP of A2780V exhibited spheroid-formation, whereas non-side-population (NSP) developed a spare monolayer growing over the healthy mesothelium. Furthermore, A2780V SP was found to be partially resistant to platinum. However, this resistance could not be explained by over-expression of the "excision repair cross-complementation group 1" (ERCC1) gene, which is essentially involved in the repair of platinated DNA damage. ERCC1 was, nonetheless, over-expressed in A2780V cells grown as spheres under stem cell-selective conditions as compared to adherent monolayers cultured under differentiating conditions. The same was true for the primary ovarian cancer cells B-57.In summary our investigations indicate that even in multi-passaged cancer cell lines hierarchic government of growth and differentiation is conserved and that the key cancer stem cell population may be composed of small overlapping cell fractions defined by various arbitrary markers.
Assuntos
Células-Tronco Neoplásicas/fisiologia , Neoplasias Ovarianas/patologia , Animais , Separação Celular , Técnicas de Cocultura , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Endonucleases/genética , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
BACKGROUND: Cow's milk is one of the most common causes of food allergy. In two-thirds of patients, adverse symptoms following milk ingestion are caused by IgE-mediated allergic reactions, whereas for one-third, the mechanisms are unknown. Aim of this study was to investigate whether patients suffering from non-IgE-mediated cow's milk protein intolerance can be distinguished from persons without cow's milk protein intolerance based on serological measurement of IgG and IgA specific for purified cow's milk antigens. METHODS: We determined IgG(1-4) subclass and IgA antibody levels to purified recombinant αS1-casein, αS2-casein, ß-casein, κ-casein, α-lactalbumin, and ß-lactoglobulin in four patient groups by ELISA: Patients with IgE-mediated cow's milk allergy (CMA, n=25), patients with non-IgE-mediated cow's milk protein intolerance (CMPI, n=19), patients with gastrointestinal symptoms not associated with cow's milk ingestion (GI, n=15) and control persons without gastrointestinal problems (C, n=26). Cow's milk-specific IgE levels were determined by ImmunoCAP. RESULTS: Only CMA patients had IgE antibodies to cow's milk. Cow's milk allergic patients mounted the highest IgG(1) and IgG(4) antibody levels to αS1-casein, αS2-casein, ß-casein, κ-casein, and α-lactalbumin. No elevated levels of IgG(4) , IgA, and complement-binding IgG subclasses (IgG(1) , IgG(2) , IgG(3) ) to purified cow's milk allergens were found within the CMPI patients compared to persons without cow's milk protein intolerance (GI and C groups). CONCLUSION: Cow's milk protein intolerant patients cannot be distinguished from persons without cow's milk protein intolerance on the basis of IgG subclass or IgA reactivity to cow's milk allergens.
Assuntos
Alérgenos/imunologia , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Hipersensibilidade a Leite/diagnóstico , Proteínas do Leite/imunologia , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Epitopos/imunologia , Feminino , Humanos , Imunoglobulina E/imunologia , Lactente , Masculino , Pessoa de Meia-Idade , Hipersensibilidade a Leite/imunologia , Ligação Proteica/imunologia , Adulto JovemRESUMO
BACKGROUND: Recent data suggest that tryptase, a mast cell enzyme, is expressed in neoplastic cells in myeloid leukaemias. In several of these patients, increased serum tryptase levels are detectable. MATERIALS AND METHODS: We have determined serum tryptase levels in 914 patients with haematological malignancies, including myeloproliferative disorders (n = 156), myelodysplastic syndromes (MDS, n = 241), acute myeloid leukaemia (AML, n = 317), systemic mastocytosis (SM, n = 81), non-Hodgkin's lymphoma (n = 59) and acute lymphoblastic leukaemia (n = 26). Moreover, tryptase was measured in 136 patients with non-neoplastic haematological disorders, 102 with non-haematological disorders and 164 healthy subjects. RESULTS: In healthy subjects, the median serum tryptase was 5.2 ng mL(-1). Elevated serum tryptase levels were found to cluster in myeloid neoplasm, whereas almost all patients with lymphoid neoplasms exhibited normal tryptase. Among myeloid neoplasms, elevated tryptase levels (> 15 ng mL(-1)) were recorded in > 90% of patients with SM, 38% with AML, 34% with CML and 25% with MDS. The highest tryptase levels, often > 1000 ng mL(-1), were found in advanced SM and core-binding-factor leukaemias. In most patients with non-neoplastic haematological disorders and non-haematological disorders analysed in our study, tryptase levels were normal, the exception being a few patients with end-stage kidney disease and helminth infections, in whom a slightly elevated tryptase was found. CONCLUSIONS: In summary, tryptase is a new diagnostic marker of myeloid neoplasms and a useful test in clinical haematology.
Assuntos
Leucemia Mieloide/metabolismo , Mastócitos/metabolismo , Síndromes Mielodisplásicas/metabolismo , Transtornos Mieloproliferativos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Triptases/genética , Adulto JovemRESUMO
The phenylaminopyrimidine-derivate Imatinib mesylate has been developed for targeted inhibition of the Abelson kinase (c-ABL), which is constitutively activated when translocated to the genetic locus of the breakpoint cluster region (leading to the BCR/ABL fusion gene), thereby forming the causative pathogenetic event for the development of chronic myeloid leukemia (CML). Of note, due to its physico-chemical properties, kinase specificity of Imatinib is limited. Despite of its well documented clinical efficacy mediated by inhibition of constitutively activated tyrosine kinases such as BCR/ABL in CML, PDGF-RA in HES and mutated c-kit in GIST patients, other tyrosine kinases such as Flt-3, Lck and mitogen-activated kinases (MAPK) are affected as well. Accordingly, it has recently been shown that therapeutic doses of Imatinib also target a variety of immune cells, e.g. by modulating the differentiation of dendritic cells (DC) as well as by impeding proper T-cell and macrophage function. In contrast, combining Imatinib with Interleukin 2 (IL-2) potently activates NK-cells and led to the description of a new subclass of DC, so-called IK-DC. The latter mediate Imatinib/IL-2-induced regression of tumors in pre-clinical animal models via production of high amounts of IFN-gamma and the death receptor ligand TRAIL. Thus, Imatinib exerts potent immuno-modulatory effects in vitro and in vivo, which will be discussed together with their clinical relevance in detail throughout this review.
Assuntos
Imunossupressores/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Benzamidas , Humanos , Mesilato de Imatinib , Imunossupressores/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêuticoAssuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , RNA Interferente Pequeno/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Benzamidas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inativação Gênica , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologiaRESUMO
BACKGROUND: Chronic inflammatory processes are thought to play a key role in the development of micro- and macrovascular complications in type 2 diabetes mellitus. An association between low -grade inflammation and type 2 diabetes has been described in some studies. We assayed the association of two frequent polymorphisms in proinflammatory cytokines: the interleukin 6 G(-174)C promoter polymorphism [IL-6G(-174)C], the exon 2 interleukin receptor antagonist insertion deletion polymorphism [IL1RA]) and serum CRP levels with the prevalence of diabetic nephropathy in patients suffering from type 2 diabetes mellitus. SUBJECTS AND METHODS: A total of 141 patients with type 2 diabetes mellitus, with and without diabetic nephropathy was genotyped for the above mentioned polymorphisms: 66 with normoalbuminuria, 31 with microalbuminuria and 44 with macroalbuminuria. CRP levels were analysed by a high sensitivity - immunnephelometric assay. RESULTS: While a significant association be-tween macroalbuminuria and CRP could be observed (p<0,015), no associations were found between IL-6G(-174)C or IL1RA genotype and any stage of nephropathy. CRP-levels were similar in the 3 different IL-6G(-174)C genotypes as well as in the 2 IL1RA genotypes. CONCLUSIONS: In type 2 diabetic subjects elevated CRP levels are associated with an increased prevalence of albuminuria. The two investigated proinflammatory polymorphisms do not seem to contribute to initiation of nephropathy in type 2 diabetic patients but we cannot exclude effects of these polymorphisms on course of nephropathy.
Assuntos
Proteína C-Reativa/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/genética , Interleucina-6/genética , Polimorfismo Genético , Idoso , Feminino , Humanos , Inflamação/sangue , Inflamação/genética , Mediadores da Inflamação/sangue , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Deleção de SequênciaRESUMO
BACKGROUND: A considerable proportion of animal-allergic patients are sensitized to both cat and dog allergens but knowledge about cross-reactive allergens in cat and dog dander is limited. OBJECTIVE: To investigate whether dog dander contains an allergen that cross-reacts with the major cat allergen, Fel d 1. METHODS: Recombinant Fel d 1 with the same immunological properties as natural Fel d 1 was used for quantitative (CAP) IgE competition experiments performed with sera obtained from cat-allergic patients (n=36). A Fel d 1 cross-reactive dog allergen was characterized by one- and two-dimensional immunoblotting using rFel d 1 for IgE inhibition experiments and with monospecific, polyclonal rabbit anti-recombinant Fel d 1 antibodies. RESULTS: In 25% of Fel d 1-reactive cat-allergic patients, more than 50% inhibition of IgE reactivity to dog allergens was achieved with recombinant Fel d 1. An Fel d 1 cross-reactive 20 kDa allergen with a pI of approximately 3.4 was detected in dander extracts of several different dog breeds. CONCLUSION: This is the first report demonstrating the presence of an Fel d 1-like allergen in dog dander extracts, which may be responsible for double positivity to cat and dog in serology. However, the clinical relevance of this cross-sensitization needs to be confirmed. These results are important for the diagnostic and therapeutic use of dog dander allergen extracts.
Assuntos
Glicoproteínas/imunologia , Hipersensibilidade/imunologia , Imunoglobulina E/sangue , Adulto , Alérgenos/imunologia , Animais , Antígenos de Plantas , Gatos , Criança , Pré-Escolar , Reações Cruzadas , Cães , Poeira , Eletroforese em Gel Bidimensional , Poluição Ambiental , Feminino , Humanos , Soros Imunes/imunologia , Soros Imunes/isolamento & purificação , Immunoblotting , Masculino , Coelhos , Proteínas Recombinantes/imunologia , Albumina Sérica/imunologia , Testes CutâneosRESUMO
Levels of the proinflammatory cytokine interleukin-6 (IL-6) are increased in therapy-resistant prostate cancer. IL-6 has been considered a positive growth factor in late-stage prostate cancer cells and a potential target for therapeutic interference. Effects of inhibition of IL-6 on cell survival were studied in LNCaP-IL6+ cells, a model system for advanced prostate cancer, which produce IL-6. We show that the autocrine IL-6 loop is responsible for resistance to apoptosis and increased cellular levels of myeloid cell leukemia-1 (Mcl-1) protein, an antiapoptotic member of the Bcl-2 family. Treatment of cells with a chimeric anti-IL-6 antibody (CNTO 328) led to the induction of apoptosis and downregulation of Mcl-1 protein levels. Specific knockdown of Mcl-1 gene expression by small interfering RNA also yielded an increase in apoptosis of LNCaP-IL-6+ cells. Vice versa, inactivation of IL-6 autocrine loop had no influence on apoptosis levels in the absence of Mcl-1, thus suggesting this molecule as a mediator of the survival action of IL-6. Mcl-1 protein regulation by the endogenous cytokine directly involved the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway. Our data support the concept of anti-IL-6 targeted therapy in therapy-resistant prostate cancer.
Assuntos
Apoptose/efeitos dos fármacos , Comunicação Autócrina , Interleucina-6/farmacologia , Proteínas de Neoplasias/fisiologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Anticorpos Monoclonais/farmacologia , Apoptose/genética , Progressão da Doença , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/imunologia , Interleucina-6/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Interferente Pequeno/farmacologia , Células Tumorais CultivadasRESUMO
BACKGROUND: Skin cholesterol (SkC) has been suggested to be an additional risk predictor, so we evaluated the test performance, potential determinants of this marker as well as a potential correlation of SkC with markers of inflammation and the history of cardiovascular events. PATIENTS AND METHODS: SkC, determined by the non-invasive PREVU POC Skin Sterol test, as well as serum lipids, the body fat status, high-sensitive CRP (hs-CRP) and serum amyloid A (SAA) were evaluated in consecutive patients with and without documented atherosclerotic disease. RESULTS: SkC was assessed in 201 patients. The within-day precision (CV) was 3.8%, the day-to-day CV of the right hand was 8.6% and 4.3% for the left hand, respectively. Neither univariate analysis nor multiple regressions identified a significant influence of age, sex, serum lipids, body fat status, smoking or diabetes mellitus on SkC, corresponding results were observed in a further analysis including 174 of these patients concerning hs-CRP and SAA (all p > 0.05). T-test analyses detected no significant differences between patients with and without a history of coronary, peripheral vascular and cerebrovascular events (all p > 0.05). CONCLUSIONS: The PREVU POC Skin Sterol test for the assessment of SkC proved an acceptable test performance. SkC is independent from serum lipids, traditional cardiovascular risk factors, two sensitive markers of systemic inflammation as well as the history of cardiovascular events indicating that the perception of this parameter as an established marker of vascular disease is premature.
Assuntos
Aterosclerose/diagnóstico , Doenças Cardiovasculares/diagnóstico , Colesterol/sangue , Mediadores da Inflamação/sangue , Pele/metabolismo , Idoso , Aterosclerose/sangue , Composição Corporal , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Valores de Referência , Medição de Risco , Fatores de Risco , Proteína Amiloide A Sérica/metabolismo , Estatística como AssuntoAssuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/fisiologia , Resistencia a Medicamentos Antineoplásicos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/efeitos dos fármacos , Animais , Benzamidas , Mesilato de Imatinib , Técnicas In Vitro , Camundongos , RNA Interferente Pequeno/farmacologiaRESUMO
BACKGROUND: Lupus anticoagulant (LA) is a strong risk factor of thrombosis. However, a subgroup of patients positive for LA is unaffected by thrombosis and currently no predictive markers are available to identify patients positive for LA at increased risk for thrombosis. OBJECTIVE: The aim of the study was to investigate whether anti-beta-2-glycoprotein I (anti-beta2GPI) or anticardiolipin antibodies (ACA) are associated with an increased risk of thrombosis in patients persistently positive for LA. PATIENTS AND METHODS: A cohort of 87 consecutive patients persistently positive for LA was investigated, 55 with and 32 without a history of thrombosis. Immunoglobulin G (IgG) and M (IgM) antibodies against beta2GPI and cardiolipin were determined by enzyme-linked immunoassay. RESULTS: Patients positive for LA with thrombosis had significantly higher levels of anti-beta2GPI IgG (median 16.7 standard units, interquartile range 3.0-75.2, P = 0.002) and of ACA IgG (41.1 IgG phospholipid units per mL, 8.9-109.0, P = 0.002) than those without thrombosis (2.6, 1.4-7.9 and 9.7, 4.6-22.1, respectively). Levels of anti-beta2GPI IgM and ACA IgM did not differ significantly between LA patients with and without thrombosis (P = 0.25 and 0.12, respectively). Elevated anti-beta2GPI IgG was associated with an increased risk for thrombosis (OR = 4.0, 95% CI 1.2-13.1), especially for venous thromboembolism (OR = 5.2, 95% CI 1.5-18.0). CONCLUSIONS: Increased levels of anti-beta2GPI IgG were associated with thrombosis. We conclude that anti-beta2GPI IgG levels above normal predict an increased risk of thrombosis in patients persistently positive for LA.
Assuntos
Autoanticorpos/sangue , Glicoproteínas/imunologia , Inibidor de Coagulação do Lúpus/sangue , Valor Preditivo dos Testes , Trombose/imunologia , Adulto , Anticorpos Anticardiolipina/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Risco , Trombose/etiologia , beta 2-Glicoproteína IRESUMO
The degree to which cerebrospinal fluid (CSF) neuron-specific enolase (NSE) contributes to the diagnosis and prognosis of disorders of the central nervous system (CNS) or peripheral nervous system (PNS) is still under debate. The aim of the study was thus to assess the validity of CSF-NSE levels in the diagnostic work-up of these conditions. The study consecutively included 106 adult patients who had undergone a diagnostic spinal tap or myelography during the diagnostic work-up for various CNS or PNS disorders. Thirty-five of these patients (16 F, 19 M, aged 24-88 years) without indication of a CNS disorder and with normal routine CSF investigations served as controls. The remaining 71 patients (31 F, 40 M, aged 28-87 years) constituted the disease group. CSF-NSE was independent of sex and age. The upper reference limit of CSF-NSE was 0.01536 ng/L. CSF-NSE was elevated in 13 of the 71 patients (18%): 6 with metabolic myopathy, 4 with polyneuropathy and 3 with hepatic encephalopathy, multiple sclerosis and paraspasticity, respectively. Only 6 of the 13 patients (46%) showed CNS involvement. The study shows that CSF-NSE is elevated in only one-fifth of unselected patients who consecutively undergo a spinal tap. CSF-NSE is elevated most frequently in patients with metabolic myopathy and polyneuropathy, even in cases without CNS abnormalities.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Fosfopiruvato Hidratase/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
HISTORY AND ADMISSION FINDINGS: A 47-year-old man with a hypereosinophilic syndrome (HES), which has been known for 20 years, was admitted to our department due to insufficient therapeutic response to hydroxyurea. In general, the patient felt well, but reported increasing neurological problems, such as ataxia, memory deficits and dysarthria. INVESTIGATIONS: Bone marrow assessments corroborated the diagnosis of a HES. However, we were not able to detect the insertional deletion 4q12 with concomitant fusion of the FIP1L1 to the PDGFRA locus. Magnetic resonance imaging (MRI) indicated a granulomatous vasculitis, which was most likely due to the hematologic malignancy. TREATMENT AND COURSE: : Despite negativity for the FIP1L1-PDGFRA fusion gene, therapy was started with the tyrosine kinase inhibitor Imatinib. This led to a rapid normalization of eosinophilic granulocytes in the peripheral blood as well as in the bone marrow. In addition, the neurologic symptoms substantially improved. CONCLUSION: Imatinib provides a potent therapeutic option in FIP1L1-PDGFRA negative patients suffering from HES.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Síndrome Hipereosinofílica/tratamento farmacológico , Piperazinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Benzamidas , Eosinófilos/efeitos dos fármacos , Humanos , Síndrome Hipereosinofílica/complicações , Síndrome Hipereosinofílica/genética , Mesilato de Imatinib , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Indução de Remissão , Vasculite do Sistema Nervoso Central/diagnóstico , Vasculite do Sistema Nervoso Central/etiologia , Fatores de Poliadenilação e Clivagem de mRNA/genéticaRESUMO
BACKGROUND: Indoor allergens derived from animals and mites often contribute to exacerbation of skin manifestations in atopic dermatitis (AD) patients. OBJECTIVE: To produce and characterize recombinant cat albumin, a cross-reactive animal allergen. METHODS: A complete cDNA coding for cat albumin was obtained by RT-PCR amplification from cat liver RNA. Recombinant cat albumin was expressed in Escherichia coli as hexahistidine-tagged protein, purified by nickel affinity chromatography and studied for IgE reactivity with sera from cat-allergic patients by ELISA and immunoblotting. Furthermore, CD203c expression of basophils from cat-allergic patients upon exposure to recombinant cat albumin was analysed. RESULTS: Recombinant cat albumin, a cross-reactive animal allergen sharing most IgE epitopes with its natural counterpart, was produced in E. coli. It was recognized preferentially by IgE from AD patients and elicited IgE-dependent basophil activation in sensitized patients. CONCLUSIONS: Recombinant cat albumin may be used as a paradigmatic tool to analyse mechanisms of allergen-triggered exacerbation of AD, for diagnostic and, perhaps for therapeutic purposes.
Assuntos
Albuminas/genética , Alérgenos/genética , Gatos/imunologia , Albuminas/imunologia , Alérgenos/imunologia , Animais , Teste de Degranulação de Basófilos , Reações Cruzadas , DNA Complementar/análise , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Immunoblotting , Imunoglobulina E , Diester Fosfórico Hidrolases/análise , Pirofosfatases/análise , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The family of transforming growth factors betas (TGF-betas) comprises molecules involved in growth inhibition, stress-induced premature senescence, epithelial mesenchymal transition and differentiation processes. The aim of this study was to clarify the effect of long term exposure of human prostate basal cells to TGF-betas, which are found in high concentrations in prostatic fluid and areas of benign prostatic hyperplasia (BPH). Basal cell cultures established from prostate explants (n=3) were either grown into cellular senescence, or stimulated with TGF-beta1, beta2 and beta3. Similar to cellular senescence, TGF-beta stimulation resulted in an increase of SA-beta galactosidase (SA-beta-gal) activity, flattened and enlarged cell morphology, and down-regulation of the inhibitor of differentiation Id-1. TGF-beta-treated prostate epithelial cells neither showed terminal growth arrest nor induction of important senescence-relevant genes, such as p16(INK4A), IFI-6-16, IGFBP-3 or Dkk-3. Cells stained positive for cytokeratins 8/18, but did not express other lumenal markers, such as prostate-specific antigen and androgen-receptors. TGF-betas increased also the expression of the mesenchymal marker vimentin, indicating that basal epithelial cells underwent differentiation with lumenal and mesenchymal features. In contrast, in vitro-differentiated neuroendocrine-like cells from prostate organoide cultures, expressing chromogranin A and cytokeratin 18, strongly stained positive for SA-beta-gal. Thus, SA-beta-gal activity is not only a marker for senescence, but also for differentiation of human prostate epithelial cells. With regard to the in vivo situation, in addition to cellular senescence, TGF-beta could contribute to the increased number of SA-beta-gal positive epithelial cells in BPH.
Assuntos
Senescência Celular/efeitos dos fármacos , Próstata/citologia , Fator de Crescimento Transformador beta/farmacologia , beta-Galactosidase/efeitos dos fármacos , Idoso , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Senescência Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genes p16 , Humanos , Masculino , Próstata/efeitos dos fármacos , Próstata/enzimologia , Proteínas Recombinantes/farmacologia , Regulação para Cima/efeitos dos fármacos , beta-Galactosidase/metabolismoRESUMO
Several studies document that allergen-specific IgE levels are boosted by allergen contact via the respiratory tract in allergic patients. Only few data are available on whether other routes of allergen contact have an influence on systemic IgE responses. We report the case of a boy who developed egg allergy after heavy consumption of eggs by the mother during pregnancy and breast feeding. In contrast to other children who outgrow egg allergy during the first years of life, the boy experienced further dramatic increases in hen egg-specific IgE antibodies after prolonged consumption of ostrich eggs containing cross-reactive allergens. IgE antibodies to most of the important respiratory allergens remained either low or not detectable. The dramatic increases in hen egg-specific IgE antibody levels after oral intake of allergens demonstrate that systemic IgE responses in allergic patients can be strongly boosted by allergen contact via routes other than the respiratory tract.