RESUMO
BACKGROUND: Testicular cancer survivors (TCS) are at risk of Leydig cell insufficiency, which is a condition characterized by elevated luteinising hormone (LH) in combination with low levels of testosterone. It has been suggested that this condition is associated with impaired metabolic profile and low bone mineral density (BMD). The primary aim of the randomized double-blind trial NCT02991209 was to evaluate metabolic profile after 12-months testosterone replacement therapy (TRT) in TCS with mild Leydig cell insufficiency. Here we present the secondary outcomes of changes in BMD and markers of bone turnover. METHODOLOGY: In total, 69 TCS with mild Leydig cell insufficiency were randomized 1:1 to 12 months TRT (n = 35) (Tostran, gel, 2%, applied transdermally, with a maximum daily dose of 40 mg) or placebo (n = 34). BMD and markers of bone turnover were evaluated at baseline, after 6- and 12-months TRT, and 3-months post-treatment. Linear mixed effects models were used to analyse changes in BMD, N-terminal propeptide of type 1 procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX). RESULTS: After 12 months treatment, TRT was not associated with a statistically significant difference in BMD compared to placebo; total body BMD: 0.01 g/cm2 (95% confidence interval (CI): -0.01 - 0.02), BMD of the lumbar spine: 0.01 g/cm2, (95% CI: -0.01-0.03), BMD of the left femoral neck: 0.00, (95% CI: -0.01-0.02). TRT was associated with a small but statistically significant increase in P1NP: 11.65 µg/L (95% CI: 3.96, 19.35), while there was no difference in CTX. CONCLUSION: 12 months of TRT did not change BMD, while there was as small and clinically irrelevant increase in P1NP compared to placebo in TCS with mild Leydig cell insufficiency. The findings need validation in a larger cohort.
Assuntos
Densidade Óssea , Neoplasias Testiculares , Masculino , Humanos , Neoplasias Testiculares/tratamento farmacológico , Testosterona/farmacologia , Testosterona/uso terapêutico , Remodelação Óssea , Sobreviventes , Método Duplo-Cego , BiomarcadoresRESUMO
STUDY QUESTION: Is anogenital distance (AGD) shorter in testicular cancer (TC) survivors than in men from the general population, and is AGD affected by testosterone replacement therapy in adulthood? SUMMARY ANSWER: AGD, measured as distance from anus to scrotum (AGDas), is shorter in TC survivors and does not change as a result of testosterone replacement therapy. WHAT IS KNOWN ALREADY: Animal studies have shown that AGD is a postnatal 'read-out' of foetal androgen action, and short AGD in male offspring is considered a sign of feminization caused by in utero disruption of the reproductive system. Likewise, measurement of AGD in human studies has suggested AGD to be part of the testicular dysgenesis syndrome hypothesis, which proposes that male reproductive disorders, such as hypospadias, cryptorchidism, some cases of impaired semen quality and TC, all share a common foetal origin. STUDY DESIGN, SIZE, DURATION: The aim was to assess AGD in men with a history of TC and controls, and furthermore to examine AGD during testosterone replacement therapy in adulthood. Study participants were TC survivors with a mild Leydig cell insufficiency who participated in a randomized double-blind study of testosterone replacement therapy versus placebo for 52 weeks (N = 69). Men from the general population were prospectively included from a study on testicular function as controls (N = 67). PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured two variants of AGD; as our primary outcome the anoscrotal distance (AGDas) measured from the centre of the anus to the posterior base of the scrotum, and secondarily the anopenile distance (AGDap) measured from the anus to the cephalad insertion of the penis. Using multiple regression analysis, the mean difference in AGD between TC survivors and men from the general population was assessed, adjusted for height, BMI and examiner. Next, AGD was measured before and after 52 weeks of treatment with testosterone or placebo, and with covariance analysis differences between the two groups at follow-up was assessed after adjustment for baseline AGD, examiner, BMI and change in BMI during treatment. MAIN RESULTS AND THE ROLE OF CHANCE: TC survivors had a shorter AGDas (-0.84 cm, 95% CI: -1.31; -0.37) compared to men from the general population, and AGDas did not differ between the testosterone and placebo treated group at follow-up (0.11 cm, 95% CI: -0.22; 0.44). In contrast, AGDap was not shorter in TC survivors after adjustment (0.05 cm, 95% CI: -0.30; 0.39), and was 0.48 cm longer (95% CI: 0.13; 0.82) at follow-up in the testosterone treated compared to the placebo-treated group. LIMITATIONS, REASONS FOR CAUTION: A limitation of the study is that the number of included men was limited, and results need confirmation in a larger study. Furthermore, TC survivors were significantly older than controls. For the comparison of AGD in TC survivors and controls, it was not possible to conduct the examinations with the examiner being blinded to which group he was examining, and it cannot be excluded that this can cause a bias. WIDER IMPLICATIONS OF THE FINDINGS: The shorter AGDas in TC survivors compared to controls, which did not change upon adult testosterone replacement therapy, supports the hypothesis that reduced AGD is part of the testicular dysgenesis syndrome and may be a marker of disrupted foetal testicular development. By contrast, AGDap was not shorter in TC survivors and might be modestly sensitive to adult testosterone treatment, and thus inferior to AGDas as a constant postnatal marker of the foetal androgen environment. STUDY FUNDING/COMPETING INTEREST(S): Expenses were paid by the Department of Oncology, Copenhagen University Hospital, Rigshospitalet. Kiowa Kirin International covered expenses for Tostran and placebo. The Danish Cancer Society, The Danish Cancer Research Foundation, the Preben & Anna Simonsen Foundation, and Rigshospitalet have supported the study. L.P. was financed by the Research Fund of the Capital Region of Denmark. The authors have no competing interests. TRIAL REGISTRATION NUMBER: Part of the study is based on men participating in a randomized controlled trial registered at ClinicalTrials.gov, NCT02991209, 25 November 2016.
Assuntos
Neoplasias Testiculares , Adulto , Canal Anal , Animais , Humanos , Masculino , Estudos Prospectivos , Análise do Sêmen , Sobreviventes , TestosteronaRESUMO
The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
Assuntos
Oncologia/normas , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Embrionárias de Células Germinativas/terapia , Guias de Prática Clínica como Assunto , Neoplasias Testiculares/terapia , Assistência ao Convalescente/métodos , Assistência ao Convalescente/normas , Sobreviventes de Câncer/psicologia , Quimiorradioterapia Adjuvante/métodos , Quimiorradioterapia Adjuvante/normas , Conferências de Consenso como Assunto , Europa (Continente) , Humanos , Masculino , Oncologia/métodos , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/normas , Recidiva Local de Neoplasia/epidemiologia , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/patologia , Orquiectomia/psicologia , Cuidados Paliativos/métodos , Cuidados Paliativos/normas , Prognóstico , Qualidade de Vida , Fatores de Risco , Terapia de Salvação/métodos , Terapia de Salvação/normas , Sociedades Médicas/normas , Sobrevivência , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/patologia , Testículo/diagnóstico por imagem , Testículo/patologia , Testículo/cirurgiaRESUMO
BACKGROUND: Twenty to thirty percent of testicular cancer (TC) survivors have elevated serum levels of luteinising hormone (LH) with or without corresponding low testosterone levels (Leydig cell dysfunction) during clinical follow-up for TC. However, it remains to be clarified if this subgroup of TC survivors has an increased long-term risk of systemic inflammation and metabolic syndrome (MetS) when compared with TC survivors with normal Leydig cell function during follow-up. PATIENTS AND METHODS: TC survivors with Leydig cell dysfunction and a control group of TC survivors with normal Leydig cell function during follow-up were eligible for participation in the study. Markers of systemic inflammation and prevalence of MetS were compared between TC survivors with Leydig cell dysfunction and the control group. RESULTS: Of 158 included TC survivors, 28 (18%) had uncompensated Leydig cell dysfunction, 59 (37%) had compensated Leydig cell dysfunction and 71 (45%) had normal Leydig cell function during follow-up. MetS and markers of systemic inflammation were evaluated at a median follow-up of 9.7 years (interquartile range 4.1-17.1) after TC treatment. The prevalence of MetS was significantly lower among patients with compensated Leydig cell dysfunction during follow-up (12% versus 27%, p = 0.04), whereas there was no difference between TC survivors with uncompensated Leydig cell dysfunction and controls (33% versus 27%, p = 0.5). Apart from high-sensitivity C-reactive protein which was higher in TC survivors with uncompensated Leydig cell dysfunction during follow-up, there was no evidence of increased systemic inflammation in patients with Leydig cell dysfunction during clinical follow-up. Total testosterone at follow-up was significantly associated with MetS, whereas there was no association between LH and MetS. CONCLUSION: We did not find evidence that TC survivors with Leydig cell dysfunction during clinical follow-up had increased long-term risk of MetS. Total testosterone at follow-up was significantly associated with MetS. The study is registered at www.clinicaltrials.govNCT02240966.
Assuntos
Inflamação/epidemiologia , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/sangue , Síndrome Metabólica/epidemiologia , Sobreviventes , Neoplasias Testiculares/terapia , Testosterona/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Dinamarca/epidemiologia , Terapia de Reposição Hormonal , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/prevenção & controle , Células Intersticiais do Testículo/patologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/prevenção & controle , Pessoa de Meia-Idade , Prevalência , Fatores de Proteção , Fatores de Risco , Testosterona/deficiência , Testosterona/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
Testicular cancer survivors have impaired gonadal function and increased risk of metabolic syndrome when compared to healthy controls. However, because of the fetal etiology of testicular cancer, familial unrelated healthy men might not be an optimal control group. The objective of this study was to clarify if testicular cancer survivors have impaired gonadal function and increased risk of metabolic syndrome when compared to their biological brothers. A cross-sectional study of testicular cancer survivors (ClinicalTrials.gov number, NCT02240966) was conducted between 2014 and 2016. Of 158 testicular cancer survivors included, 24 had a biological brother who accepted to participate in the study. Serum levels of reproductive hormones and prevalence of metabolic syndrome according to International Diabetes Federation Criteria and National Cholesterol Education Program (Adult Treatment Panel III) criteria comprised the main outcome measures of the study. Median age was similar in testicular cancer survivors and their biological brothers [44 years (IQR 39-50) vs. 46 (40-53) years respectively (p = 0.1)]. In testicular cancer survivors, follow-up since treatment was 12 years (7-19). Serum levels of luteinizing hormone and follicle-stimulating hormone were elevated (p ≤ 0.001), while total testosterone, free testosterone, inhibin B and anti-Müllerian hormone were lower (p ≤ 0.001) in testicular cancer survivors than in their biological brothers. The prevalence of metabolic syndrome was similar and apart from HDL-cholesterol, which was lower in testicular cancer survivors (p = 0.01); there were no differences in the individual components of the metabolic syndrome between testicular cancer survivors and their brothers. In conclusion, gonadal function was impaired in testicular cancer survivors, while we did not detect any difference in the prevalence of metabolic syndrome between testicular cancer survivors and their biological brothers.
Assuntos
Sobreviventes de Câncer , Hormônios/sangue , Síndrome Metabólica/sangue , Reprodução , Irmãos , Neoplasias Testiculares/terapia , Testículo/metabolismo , Absorciometria de Fóton , Adipocinas/sangue , Adulto , Hormônio Antimülleriano/sangue , Biomarcadores/sangue , Estudos Transversais , Dinamarca/epidemiologia , Hormônio Foliculoestimulante/sangue , Humanos , Mediadores da Inflamação/sangue , Inibinas/sangue , Lipídeos/sangue , Hormônio Luteinizante/sangue , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Espermatogênese , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/fisiopatologia , Testículo/fisiopatologia , Testosterona/sangue , Fatores de TempoRESUMO
Results concerning treatment of Testicular Germ Cell Cancer (TGCC) and subsequent risk of testosterone deficiency are conflicting. To systematically evaluate and estimate the risk of testosterone deficiency (TD) in TGCC-patients according to treatment to optimize follow-up and for prevention of late effects related to hypogonadism. We performed a critical review of PubMed in January 2015 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Twelve publications were selected for inclusion in this analysis. Eleven studies evaluated the risk of TD in TGCC-patients treated with standard chemotherapy (CT) and the odds ratio for TD was 1.8 (95% CI) (1.3-2.5), (p = 0.0007). Seven studies evaluated the risk of TD in TGCC-patients treated with non-conventional therapy and the odds ratio for TD was 3.1 (95% CI) (2.0-4.8), (p < 0.0001). Six studies evaluated the risk of TD in TGCC-patients treated with infradiaphragmatic radiotherapy (RT), and the odds ratio for TD was 1.6 (95% CI) (1.0-2.4), (p = 0.03). In all treatment groups the risk of TD was compared with TGCC-patients treated with orchiectomy alone. There was no indication of heterogeneity between studies in the three treatment groups. Strong evidence exists that standard CT, non-conventional therapy and infradiaphragmatic RT are associated with an increased risk of TD in TGCC-patients when compared with orchiectomy alone. The risk of testosterone defficiency appears to be highest in patients treated with non-conventional therapy.
Assuntos
Hipogonadismo/etiologia , Orquiectomia/efeitos adversos , Neoplasias Testiculares/complicações , Testosterona/deficiência , Humanos , Hipogonadismo/sangue , Masculino , Sobreviventes , Neoplasias Testiculares/sangueRESUMO
BACKGROUND: Screening programmes for contralateral carcinoma in situ (CIS) testis in patients with unilateral germ-cell cancer (GCC) have never been evaluated. We investigated the effect of screening for contralateral CIS in a large nation-wide, population-based study. PATIENTS AND METHODS: A contralateral single-site biopsy was offered to 4130 patients in whom GCC had been diagnosed in 1984-2007 (screened cohort); 462 patients in whom GCC was diagnosed in 1984-1988 comprised the unscreened cohort. Cases with CIS were offered radiotherapy. Initially CIS-negative biopsies in patients with metachronous GCC were revised according to today's standards. Risk for metachronous GCC was estimated using cumulative incidence and the Cox proportional hazards model. RESULTS: In the screened cohort, contralateral CIS was found in 181 (4.4%) patients. The cumulative incidence of metachronous GCC after 20 years was 1.9% in the screened cohort and 3.1% in the unscreened cohort (P = 0.097), hazard ratio (HR) for the unscreened cohort: 1.59 (P = 0.144). Expert revision with contemporary methodology of CIS-negative biopsy samples from patients with metachronous cancer revealed CIS in 17 out of 45 (38%) cases. Decreased risks for metachronous GCC were related to older age at diagnosis (HR 0.52 per 10 years, P < 0.001) and chemotherapy (HR 0.35, P = 0.002). Limitations include the small number of patients in the unscreened cohort and the retrospective study design. CONCLUSIONS: Our evaluation of a national population-based screening programme for contralateral CIS in patients with testicular cancer showed no significant difference in the risk for metachronous GCC between a screened and an unscreened cohort. Single-site biopsy including modern immunohistochemistry does not identify all cases of CIS.
Assuntos
Carcinoma in Situ/diagnóstico , Carcinoma in Situ/epidemiologia , Detecção Precoce de Câncer , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Testiculares/epidemiologia , Adulto , Carcinoma in Situ/terapia , Estudos de Coortes , Terapia Combinada , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Primárias Múltiplas/terapia , Prognóstico , Medição de Risco , Neoplasias Testiculares/patologia , Neoplasias Testiculares/terapiaRESUMO
BACKGROUND: Treatment with bleomycin-etoposide-cisplatin (BEP) impairs renal function and increases the risk of late cardiovascular disease (CVD) and death. We investigated the influence of BEP on glomerular filtration rate (GFR) and assessed the importance of GFR changes on CVD and death in a large cohort of germ-cell cancer survivors. PATIENTS AND METHODS: BEP-treated patients (N = 1206) were identified in the Danish DaTeCa database, and merged with national registers to identify late toxicity. GFR were measured (51Cr-EDTA clearance) before and after treatment and at 1, 3 and 5-year follow-up. The influence of BEP on GFR was evaluated with a linear mixed model. Risk factors for late toxicity were identified by a landmark analysis adjusting for covariates. The cohort was compared with the background population with standardized hospitalization/mortality rates. RESULTS: GFR changed (ΔGFR) -11.3%, -15.4% and -25.9% after three, four and five+ cycles of BEP. For patients with impaired renal function before treatment the changes were 4.3%, 0.0% and -12.8%, respectively. During follow-up a significant rebound of GFR was documented. Compared with the background population, all patients, irrespective of renal function, had an increased risk of CVD and death. This risk depended on chronic kidney disease stage before treatment but not after treatment. ΔGFR had no influence on risk of late toxicity [death: hazard ratio (HR) 1.06, P = 0.50; CVD: HR 0.97, P = 0.61]. CONCLUSIONS: Renal function after BEP is closely related to number of cycles, but the changes in GFR are partly reversible and have no impact on risk of CVD or death.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Insuficiência Renal/induzido quimicamente , Adolescente , Adulto , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Regulatory T (Treg) cells are important for the maintenance of peripheral tolerance and inhibition of pathogenic T-cell responses. Therefore, they are important for the limitation of chronic inflammation but can also be deleterious by e.g. limiting antitumour immune responses. Natural occurring Tregs are known to inhibit CD4+ T cell in a contact-dependent manner, but at the same time, various suppressive factors are secreted. We, here, demonstrate that human naturally occurring CD4+CD25+ Tregs are able to shed large amounts of soluble CD25 upon activation. Secretion of sCD25 could add to the inhibitory effect of Tregs as such secretion in other settings has been proposed to act as a sink for local IL-2. However, we here demonstrate that supernatant from human Tregs containing high concentration of sCD25 does not inhibit proliferation of CD4+CD25(-) T cells or inhibit the action of IL-2 in an in vitro bioassay.
Assuntos
Tolerância Imunológica/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-2/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Antígenos CD4/imunologia , Proliferação de Células , Humanos , Interleucina-2/metabolismo , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
BACKGROUND: Unenhanced multidetector computed tomography (UMDCT) is well established as the procedure of choice for radiologic evaluation of patients with renal colic. The procedure has both clinical and financial consequences for departments of surgery and radiology. However, the financial effect outside the radiology department is poorly elucidated. PURPOSE: To evaluate the financial consequences outside of the radiology department, a retrospective study comparing the ward occupation of patients examined with UMDCT to that of intravenous urography (IVU) was performed. MATERIAL AND METHODS: A total of 594 consecutive patients were admitted for renal colic during two 6-month periods. One hundred seventy-three consecutive patients were examined with IVU in 2000 and 421 with UMDCT in 2005. The only difference between the two groups was the imaging procedure. The duration of hospital stay and pathology findings were registered. RESULTS: In 50% of the patients undergoing UMDCT, a stone was found; a stone was found or suspected in 40% of patients undergoing IVU. Patients undergoing IVU stayed significantly longer in the ward than patients examined by UMDCT (P<0.0001). The new procedure (UMDCT) saved the hospital USD 265,000 every 6 months compared to the use of IVU. CONCLUSION: Use of UMDCT compared to IVU in patients with renal colic leads to cost savings outside the radiology department.
Assuntos
Cólica/diagnóstico , Nefropatias/diagnóstico , Tempo de Internação/economia , Serviço Hospitalar de Radiologia/estatística & dados numéricos , Tomografia Computadorizada por Raios X/economia , Tomografia Computadorizada por Raios X/métodos , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Urografia/economia , Urografia/métodos , Adulto JovemRESUMO
Melanoma antigen recognized by T cell 1 (MART-1) is regarded as a candidate peptide for vaccination against malignant melanoma, and it is of importance to develop strategies to improve the vaccine-elicited T-cell activation towards MART-1. T-cell activation is, among other determinants, dependent on the density of specific major histocompatibility complex-peptide complexes on the surface of the antigen-presenting cell. In this study, we explored the cell-surface presentation of a substituted MART-1 peptide encoded by transfected minigenes. We investigated the potential of proteasomal targeting compared to non-proteasomal targeting of the epitope to increase its cell-surface presentation. Furthermore, we explored the potential of incorporating multiple minigenes instead of one to increase cell-surface presentation. We show that both proteasomal targeting and repetition of the minigene increase cell-surface presentation of the epitope and propose both these approaches as potential strategies in DNA vaccines to increase MART-1-specific T-cell activation.
Assuntos
Vacinas Anticâncer/imunologia , Cisteína Endopeptidases/imunologia , Melanoma/imunologia , Complexos Multienzimáticos/imunologia , Proteínas de Neoplasias/imunologia , Sequência de Aminoácidos , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Antígenos de Neoplasias , Western Blotting , Vacinas Anticâncer/genética , Linhagem Celular , Cisteína Endopeptidases/genética , Testes Imunológicos de Citotoxicidade , Epitopos/imunologia , Humanos , Antígeno MART-1 , Melanoma/terapia , Dados de Sequência Molecular , Complexos Multienzimáticos/genética , Proteínas de Neoplasias/genética , Plasmídeos/genética , Plasmídeos/imunologia , Reação em Cadeia da Polimerase , Complexo de Endopeptidases do Proteassoma , Sequências Repetitivas de Ácido Nucleico , Linfócitos T/imunologia , Transfecção , Vacinas de DNA/imunologiaRESUMO
Regulation of T-cell receptor (TCR) cell surface expression levels is probably an important mechanism by which T-cell responsiveness is controlled. Previously, two distinct pathways for TCR downregulation have been described. One is dependent on protein kinase C (PKC) and the leucine-based receptor-sorting motif (L-based motif) of the CD3 gamma chain but independent of tyrosine kinases, whereas the other is dependent on the tyrosine kinase activation but independent of the PKC and the CD3 gamma L-based motif. In this study, we describe a new pathway for TCR downregulation distinct from both the PKC/CD3 gamma L-based motif-dependent and the tyrosine kinase-dependent pathways. This pathway is dependent on ceramide-induced activation of caspases and correlate with caspase-mediated cleavage of the zeta chain. Thus, a 10--15% downregulation of the TCR was induced following the treatment of the T cells with ceramide for 4 h. A close correlation between TCR downregulation, caspase activation, and cleavage of the zeta chain was found. Furthermore, the caspase inhibitors abolished the cleavage of the zeta chain and TCR downregulation in parallel with the inhibition of the caspase activity.
Assuntos
Caspases/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Receptores de Antígenos de Linfócitos T/biossíntese , Receptores de Antígenos de Linfócitos T/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Substituição de Aminoácidos , Apoptose/efeitos dos fármacos , Sítios de Ligação , Inibidores de Cisteína Proteinase/farmacologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Células Jurkat/efeitos dos fármacos , Células Jurkat/enzimologia , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Oligopeptídeos/farmacologia , Proteínas Tirosina Quinases/fisiologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T gama-delta/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/química , Receptores de Antígenos de Linfócitos T gama-delta/genética , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , TransfecçãoRESUMO
This paper presents further international comparisons of progressivity of health care financing systems. The paper builds on the work of Wagstaff et al. [Wagstaff, A., van Doorslaer E., et al., 1992. Equity in the finance of health care: some international comparisons, Journal of Health Economics 11, pp. 361-387] but extends it in a number of directions: we modify the methodology used there and achieve a higher degree of cross-country comparability in variable definitions; we update and extend the cross-section of countries; and we present evidence on trends in financing mixes and progressivity.
Assuntos
Política de Saúde/economia , Programas Nacionais de Saúde/economia , Justiça Social , Impostos/classificação , Comparação Transcultural , Europa (Continente) , Finlândia , Alemanha , Pesquisa sobre Serviços de Saúde , Humanos , Renda/estatística & dados numéricos , Seguro Saúde/economia , Suécia , Impostos/economia , Impostos/estatística & dados numéricosRESUMO
The OECD countries finance their health care through a mixture of taxes, social insurance contributions, private insurance premiums and out-of-pocket payments. The various payment sources have very different implications for both vertical and horizontal equity and on redistributive effect which is a function of both. This paper presents results on the income redistribution consequences of the health care financing mixes adopted in twelve OECD countries by decomposing the overall income redistributive effect into a progressivity, horizontal inequity and reranking component. The general finding of this study is that the vertical effect is much more important than horizontal inequity and reranking in determining the overall redistributive effect but that their relative importance varies by source of payment. Public finance sources tend to have small positive redistributive effects and less differential treatment while private financing sources generally have (larger) negative redistributive effects which are to a substantial degree caused by differential treatment.
Assuntos
Política de Saúde/economia , Programas Nacionais de Saúde/economia , Justiça Social , Impostos/classificação , Comparação Transcultural , Europa (Continente) , Financiamento Pessoal/estatística & dados numéricos , Pesquisa sobre Serviços de Saúde , Humanos , Seguro Saúde/economia , Modelos Econométricos , Impostos/economia , Impostos/estatística & dados numéricosRESUMO
This study analysed the impact of several factors on the start and duration of time off work among 802 patients with occupational hand injuries, in order to identify prognostic indicators. The study showed that external factors such as work and social condition seemed to have less influence on time off work than expected, whereas advice from doctors, flashbacks and impairment symptoms were important determinants.
Assuntos
Traumatismos da Mão , Doenças Profissionais , Licença Médica , Atitude Frente a Saúde , Dinamarca , Humanos , Razão de Chances , Prognóstico , Fatores de TempoRESUMO
TCR down-regulation plays an important role in modulating T cell responses both during T cell development and in mature T cells. Down-regulation of the TCR is induced by engagement of the TCR by specific ligands and/or by activation of protein kinase C (PKC). We report here that ligand- and PKC-induced TCR down-regulation is mediated by two distinct, independent mechanisms. Ligand-induced TCR down-regulation is dependent on the protein tyrosine kinases p56(lck) and p59(fyn) but independent of PKC and the CD3gamma leucine-based (L-based) internalization motif. In contrast, PKC-induced TCR down-regulation is dependent on the CD3gamma L-based internalization motif but independent of p56(lck) and p59(fyn). Finally, our data indicate that in the absence of TCR ligation, TCR expression levels can be finely regulated via the CD3gamma L-based motif by the balance between PKC and serine/threonine protein phosphatase activities. Such a TCR ligation-independent regulation of TCR expression levels could probably be important in determining the activation threshold of T cells in their encounter with APC.
Assuntos
Regulação para Baixo/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Sequência de Aminoácidos , Humanos , Células Jurkat , Ligantes , Dados de Sequência Molecular , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-fyn , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/biossíntese , Linfócitos T/enzimologia , Tirosina/metabolismo , Quinases da Família src/fisiologiaRESUMO
Use of NSAIDs is recognized as an important cause of peptic ulcer complications. The aim of this nested case-control study was to identify risk factors for NSAID-related ulcer complications. Cases were consecutive NSAID users admitted with an ulcer complication (n = 94), and controls were a random sample of all NSAID users without ulcer complication identified by a pharmaco-epidemiological database (n = 324). Risk factors for patients at start of NSAID-therapy were: high age: 60-75 yr; Odds Ratio (OR) 3.5 (95% CI: 1.8-7.0); > 75 yr: OR 8.8 (4.3-18.1); male sex: OR 1.7 (1.0-3.0); ulcer history: OR 2.5 (1.2-5.1); steroid treatment: OR 2.0 (0.8-4.6); smoking: OR 1.6 (0.9-2.7); alcohol use: OR 1.8 (0.9-3.6). Risk factors for patients on NSAID-therapy were: high age, male sex, ulcer history, and smoking, and furthermore dyspepsia: OR 2.1 (1.0-4.2), especially NSAID-related dyspepsia: OR 8.9 (4.1-19.2). Risk was lower for patients treated more than three months. In conclusion, risk measured from this design can be shown to correlate strongly with the rate difference, a measure that is more clinically relevant than conventional relative risk estimates. Strong risk factors for NSAID-related ulcer complication are high age, male sex, ulcer history, and dyspepsia related to the NSAID therapy.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Úlcera Gástrica/induzido quimicamente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica Hemorrágica/induzido quimicamente , FarmacoepidemiologiaRESUMO
STUDY DESIGN: Cross-sectional data were collected in a postal questionnaire within the framework of a 5-year randomized, controlled, prospective, population-based study. OBJECTIVES: To investigate to what extent associations differ or concur when correlates of low back pain are rested against various subdefinitions of low back pain. SUMMARY OF BACKGROUND DATA: Numerous factors have been suspected to cause low back pain, but findings have not been constantly reproduced in epidemiologic studies. METHODS: Data were collected on 748 people reporting nonspecific low back pain some time during the year preceding the survey. Six correlates of low back pain (age, sex, marital status, attitude to a healthy life-style, self-reported physical activity at work, and smoking) were cross-tabulated against nonspecific low back pain and against four subgroups of low back pain. RESULTS: There was only one statistically significant strong association between the potential risk indicators and the nonspecific definition of low back pain, but several emerged when the low back pain group was split into subgroups. Different subgroups of low back pain did, indeed, relate differently to the various correlates. CONCLUSIONS: It is necessary to define some clinically relevant subgroups of low back pain to accelerate the search for causal mechanisms.
Assuntos
Dor Lombar/epidemiologia , Dor Lombar/etiologia , Adulto , Estudos Transversais , Coleta de Dados , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cervicalgia/epidemiologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Fatores de TempoRESUMO
The cancer incidence in a historical cohort of 10,059 metal workers employed during the period 1964-1984 was investigated. Standardized incidence ratios (SIR) were calculated based on registry extracts from the Danish Cancer registry. Lifetime exposure data (occupational and other) were obtained by a postal questionnaire in living cohort members and interviews by proxy for deceased and emigrated subjects. The incidence of lung cancer was increased among workers ever "employed as welders" (SIR = 1.38, 95% C.I. 1.03-1.81). There was a significant excess risk of lung cancer among "mild steel (MS) only welders" (SIR = 1.61, 95% C.I. 1.07-2.33) and "nonwelders" (SIR = 1.69, 95% C.I. 1.23-2.26) (indicating carcinogenic exposures other than welding), a borderline significant lung cancer excess among "MS ever welders" (SIR = 1.32, 95% C.I. 0.97-1.76), and a nonsignificant excess risk of lung cancer among "stainless steel (SS) only welders" (SIR = 2.38, 95% C.I. 0.77-5.55). In spite of signs of inconsistency in the risk estimation by duration and latency, we find the results support the conclusions of other studies: employment as a welder is associated with an increased lung cancer risk.
Assuntos
Metalurgia , Neoplasias/epidemiologia , Doenças Profissionais/epidemiologia , Aço Inoxidável , Aço , Soldagem , Amianto/efeitos adversos , Carcinógenos/efeitos adversos , Estudos de Coortes , Dinamarca/epidemiologia , Emprego , Exposição Ambiental , Seguimentos , Humanos , Incidência , Entrevistas como Assunto , Neoplasias Pulmonares/epidemiologia , Masculino , Exposição Ocupacional , Sistema de Registros , Fatores de Risco , Fumar/efeitos adversos , Inquéritos e QuestionáriosRESUMO
The association between welding and lung cancer has been studied in a nested case-referent study within a cohort of 8,372 metal workers. Lifetime exposure data on welding and other occupational exposures, as well as alcohol and smoking habits, were obtained by interviews of spouses and colleagues. Analysis was based on 439 deceased referents and 94 deceased cases. There was a 70% excess of lung cancer associated with "welding exposure ever" (OR +/- 95% C.I.: 1.68, 1.02-2.78). Overall OR for "mild steel (MS) welding ever" was 1.64, 0.99-2.72. The risk estimates for welding exposures showed an increasing tendency up to 15 years of exposure. The pattern of stainless steel (SS) welding resembles that of mild steel with an estimated OR of 1.65, 0.88-3.0. The general conclusion is that MS welding as well as SS welding seems to be associated with an increased risk of lung cancer. Further followup of the cohort will enhance precision of the estimates.