RESUMO
A 27-year old caucasian male was diagnosed 2.7 years after kidney transplantation with Epstein-Barr virus (EBV)-associated smooth muscle tumors in liver and spleen. The reduction in immunosuppression and conversion from tacrolimus to sirolimus did not lead to a regression of the tumors. Additionally, the patient developed a cellular rejection of his renal allograft, which was successfully treated. A combined approach with stereotactic radiofrequency ablation (SRFA) and surgical resection was effective in the treatment of the tumors.
Assuntos
Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/isolamento & purificação , Transplante de Rim/efeitos adversos , Tumor de Músculo Liso/etiologia , Tumor de Músculo Liso/virologia , Adulto , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/etiologia , Rejeição de Enxerto , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Fígado/patologia , Fígado/virologia , Masculino , Radiocirurgia , Sirolimo/uso terapêutico , Tumor de Músculo Liso/cirurgia , Baço/patologia , Baço/virologia , Tacrolimo/uso terapêutico , Resultado do TratamentoRESUMO
Novel biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes have been recently identified. We performed a systematic review to assess the validity of biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes in longitudinal studies. The methodological quality of the studies was scored using Standards for Reporting of Diagnostic Accuracy (STARD) criteria and the independent predictive value of the biomarkers beyond conventional risk factors was scored according to the adjustment for these risk factors. Validity of the biomarkers was determined by summarizing the methodological quality and the adjustment score. We identified 15 studies describing 27 biomarkers. Six studies had sufficient methodological quality. These studies identified 13 valid and significant markers for nephropathy in diabetes: serum interleukin 18, plasma asymmetric dimethylarginine; and urinary ceruloplasmin, immunoglobulin G and transferrin were considered valid markers predicting onset of nephropathy. Plasma asymmetric dimethylarginine, vascular cell adhesion molecule 1, interleukin 6, von Willebrand factor and intercellular cell adhesion molecule 1 were considered valid biomarkers predicting progression of nephropathy. Plasma high-sensitivity C-reactive protein, E-selectin, tissue-type plasminogen activator, von Willebrand factor and triglycerides were considered valid markers predicting onset and progression of nephropathy. Several novel biomarkers for prediction of nephropathy in diabetes have been published, which can potentially be applied in clinical practice and research in future. Because of the heterogeneous quality of biomarker studies in this field, a more rigorous evaluation of these biomarkers and validation in larger trials are advocated.
Assuntos
Albuminúria/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Albuminúria/sangue , Albuminúria/urina , Biomarcadores/sangue , Biomarcadores/urina , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/cirurgia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/urina , Progressão da Doença , Endotélio Vascular , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Molécula 1 de Adesão Intercelular/urina , Interleucina-6/sangue , Interleucina-6/urina , Masculino , Valor Preditivo dos Testes , Molécula 1 de Adesão de Célula Vascular/sangue , Molécula 1 de Adesão de Célula Vascular/urina , Fator de von Willebrand/urinaRESUMO
BACKGROUND: In patients with multiple myeloma (MM) free light chain-induced cast nephropathy is a serious complication associated with poor survival. High-cut-off (HCO) hemodialysis can reduce the amount of serum free light chains (sFLC), but data on its impact on clinical outcome is limited and contradictory. To gain further insights we collected real world data from two major myeloma and nephrology centers in Austria and the Czech Republic. METHODS: Sixty-one patients with MM and acute kidney injury, who were treated between 2011 and 2019 with HCO hemodialysis and bortezomib-based MM therapy, were analyzed. RESULTS: The median number of HCO hemodialysis sessions was 11 (range 1-42). Median glomerular filtration rate at diagnosis was 7 ± 4.2 ml/min/1.73m2. sFLC after the first HCO hemodialysis decreased by 66.5% and by 89.2% at day 18. At 3 and 6 months, 26 (42.6%) and 30 (49.2%) of patients became dialysis-independent. CONCLUSION: The widely used strategy combining HCO hemodialysis and bortezomib-based antimyeloma treatment is dissatisfactory for half of the patients undergoing it and clearly in need of improvement.
Assuntos
Injúria Renal Aguda , Mieloma Múltiplo , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/terapia , Bortezomib/efeitos adversos , Humanos , Cadeias Leves de Imunoglobulina , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Diálise Renal/efeitos adversosRESUMO
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
Novel drugs like Abiraterone or Enzalutamide, which target androgen receptor (AR) signaling to improve androgen deprivation therapy (ADT), have been developed during the past years. However, the application of these drugs is limited because of occurrence of inherent or acquired therapy resistances during the treatment. Thus, identification of new molecular targets is urgently required to improve current therapeutic prostate cancer (PCa) treatment strategies. PIAS1 (protein inhibitor of activated STAT1 (signal transducer and activator of transcription-1)) is known to be an important cell cycle regulator and PIAS1-mediated SUMOylation is essential for DNA repair. In this context, elevated PIAS1 expression has already been associated with cancer initiation. Thus, in the present study, we addressed the question of whether PIAS1 targeting can be used as a basis for an improved PCa therapy in combination with anti-androgens. We show that PIAS1 significantly correlates with AR expression in PCa tissue and in cell lines and demonstrate that high PIAS1 levels predict shorter relapse-free survival. Our patient data are complemented by mechanistic and functional in vitro experiments that identify PIAS1 as an androgen-responsive gene and a crucial factor for AR signaling via prevention of AR degradation. Furthermore, PIAS1 knockdown is sufficient to decrease cell proliferation as well as cell viability. Strikingly, Abiraterone or Enzalutamide treatment in combination with PIAS1 depletion is even more effective than single-drug treatment in multiple PCa cell models, rendering PIAS1 as a promising target protein for a combined treatment approach to improve future PCa therapies.
Assuntos
Retroalimentação Fisiológica , Neoplasias da Próstata/patologia , Proteínas Inibidoras de STAT Ativados/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Androgênios/farmacologia , Androstenos/farmacologia , Benzamidas , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Retroalimentação Fisiológica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Masculino , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Inibidoras de STAT Ativados/deficiência , Proteínas Inibidoras de STAT Ativados/genética , Estabilidade Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Transcrição Gênica/efeitos dos fármacosRESUMO
PURPOSE: Suppressors of cytokine signalling (SOCS) are induced by interleukins and peptide hormones. These molecules prevent the activation of diverse signalling pathways in benign and malignant cells. In previous studies, we showed that SOCS-3 is expressed in most prostate cancer cell lines and tissue specimens. In the present study we investigated the effects of androgen on the regulation of SOCS-3 in prostate cancer cell lines. MATERIALS AND METHODS: SOCS-3 expression was determined with PCR and Western blot techniques. The activity of the SOCS-3 promoter was measured with the luciferase test. We measured proliferation with (3)H-thymidine assay. RESULTS: We show that androgen induces the expression of SOCS-3 in two prostate cancer cell lines. The non-steroidal anti-androgen bicalutamide is able to block the induction of SOCS-3 -expression. Androgenic hormones did not induce the expression of SOCS-3 mRNA or its promoter activity. In LNCaP-IL-6- cells transfected with the inducible Tet-On construct SOCS-3 expression was induced. The effects of androgenic hormones on the proliferation and induction of PSA were -diminished in the presence of SOCS-3. CONCLUSIONS: Our results show that androgenic -regulation of SOCS-3 leads to inhibition of prolif-eration and secretion in human prostate cancer.
Assuntos
Antagonistas de Androgênios/farmacologia , Androgênios/fisiologia , Anilidas/farmacologia , Divisão Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Nitrilas/farmacologia , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Supressoras da Sinalização de Citocina/genética , Compostos de Tosil/farmacologia , Biomarcadores Tumorais/metabolismo , Western Blotting , Quinases Ciclina-Dependentes/genética , Doxiciclina/farmacologia , Humanos , Interleucina-6/metabolismo , Masculino , Metribolona/farmacologia , Reação em Cadeia da Polimerase , Antígeno Prostático Específico/metabolismo , RNA Mensageiro/genética , Proteína 3 Supressora da Sinalização de Citocinas , Congêneres da Testosterona/farmacologia , Transfecção , Células Tumorais CultivadasRESUMO
PURPOSE: Human prostate development starts in the tenth week of gestation. Initial interactions between the epithelium and mesenchyma are stimulated by androgens. The transformation of circulating testosterone to 5alpha-dihydrotestosterone by tissue linked 5alpha-reductase is a key event in androgen metabolism. The 5alpha-dihydrotestosterone mediates androgen effects in the urogenital sinus and external genitalia, leading to the formation of a male phenotype and androgen mediated prostate growth. Supposedly 5alpha-reductase 2 is the predominant isoenzyme in human accessory sex tissue, whereas the function of 5alpha-reductase 1 remains unclear. We focused on the detection, distribution and effects of the 2 isoenzymes during gestation and infancy. MATERIALS AND METHODS: Serial sections from fetuses and infants were immunostained using antibodies directed against 5alpha-reductase 1 and 2. Additionally, to detect the downstream products of androgen synthesis reverse transcriptase-polymerase chain reaction analyses were done for 17 beta-hydroxysteroid dehydrogenase types 2, 3 and 7. RESULTS: Immunohistochemistry revealed positive staining for each isoenzyme throughout fetal development. Moreover, reverse transcriptase-polymerase chain reaction for 5alpha-reductase 1 and 2 confirmed these findings on the transcription level. Additionally, the most relevant enzymatic downstream products of cellular androgen synthesis (17 beta-hydroxysteroid dehydrogenase 2, 3 and 7) were also detected by reverse transcriptase-polymerase chain reaction. CONCLUSIONS: To our knowledge this is the first study revealing the expression and distribution of each 5alpha-reductase isoenzyme as well as the potential contribution of 5alpha-reductase 1 during fetal human prostate development.