RESUMO
The active site of the [FeFe]-hydrogenase ([FeFe]-H2ase) has a bridging carbonyl ligand and a terminal hydride in the key H-cluster intermediate Hhyd. However, nearly all of the synthetic mimics reported, so far, prefer a hydride bridging the two irons, and only few mimics with a terminal hydride were achieved by tuning the steric effects of bulky diphosphine ligands. Moreover, although intermediates with either a terminal hydride or a protonated bridging thiolate ligand were proposed to exist during protonation processes or hydrogen exchange in the [FeFe]-H2ase mimic, [Fe2(µ-pdt)(µ-H)(CO)4(PMe3)2]+ (1H+), only bridging hydrides were observed by time-resolved IR spectroscopy. In this report, FTIR spectroscopy of 1H+, under CO with longer irradiation time, revealed several new photoinduced species. In addition to the CO loss species, many of the photoinduced products can be assigned to 1H+ with a terminal hydride by comparison of their CO vibrational frequencies with density functional theory calculations.
RESUMO
PURPOSE: With successive infection waves and the spread of more infectious variants, the COVID-19 pandemic continues to have major impacts on health care. To achieve best outcomes for patients with cancer during a pandemic, efforts to minimize the increased risk of severe pandemic infection must be carefully balanced against unintended adverse impacts of the pandemic on cancer care, with consideration to available health system capacity. Cancer Australia's conceptual framework for cancer care during a pandemic provides a planning resource for health services and policy-makers that can be broadly applied globally and to similar pandemics. METHODS: Evidence on the impact of the COVID-19 pandemic on cancer care and health system capacity to June 2021 was reviewed, and the conceptual framework was developed and updated. RESULTS: Components of health system capacity vary during a pandemic, and capacity relative to pandemic numbers and severity affects resources available for cancer care delivery. The challenges of successive pandemic waves and high numbers of pandemic cases necessitate consideration of changing health system capacity in decision making about cancer care. Cancer Australia's conceptual framework provides guidance on continuation of care across the cancer pathway, in the face of challenges to health systems, while minimizing infection risk for patients with cancer and unintended consequences of delays in screening, diagnosis, and cancer treatment and backlogs because of service interruption. CONCLUSION: Evidence from the COVID-19 pandemic supports continuation of cancer care wherever possible during similar pandemics. Cancer Australia's conceptual framework, underpinned by principles for optimal cancer care, informs decision making across the cancer care continuum. It incorporates consideration of changes in health system capacity and capacity for cancer care, in relation to pandemic progression, enabling broad applicability to different global settings.
Assuntos
COVID-19 , Neoplasias , Atenção à Saúde , Programas Governamentais , Humanos , Neoplasias/terapia , Pandemias/prevenção & controle , SARS-CoV-2RESUMO
BACKGROUND: Growth hormone is widely abused by athletes, frequently with androgenic steroids. Its effects on performance are unclear. OBJECTIVE: To determine the effect of growth hormone alone or with testosterone on body composition and measures of performance. DESIGN: Randomized, placebo-controlled, blinded study of 8 weeks of treatment followed by a 6-week washout period. Randomization was computer-generated with concealed allocation. (Australian-New Zealand Clinical Trials Registry registration number: ACTRN012605000508673) SETTING: Clinical research facility in Sydney, Australia. PARTICIPANTS: 96 recreationally trained athletes (63 men and 33 women) with a mean age of 27.9 years (SD, 5.7). INTERVENTION: Men were randomly assigned to receive placebo, growth hormone (2 mg/d subcutaneously), testosterone (250 mg/wk intramuscularly), or combined treatments. Women were randomly assigned to receive either placebo or growth hormone (2 mg/d). MEASUREMENTS: Body composition variables (fat mass, lean body mass, extracellular water mass, and body cell mass) and physical performance variables (endurance [maximum oxygen consumption], strength [dead lift], power [jump height], and sprint capacity [Wingate value]). RESULTS: Body cell mass was correlated with all measures of performance at baseline. Growth hormone significantly reduced fat mass, increased lean body mass through an increase in extracellular water, and increased body cell mass in men when coadministered with testosterone. Growth hormone significantly increased sprint capacity, by 0.71 kJ (95% CI, 0.1 to 1.3 kJ; relative increase, 3.9% [CI, 0.0% to 7.7%]) in men and women combined and by 1.7 kJ (CI, 0.5 to 3.0 kJ; relative increase, 8.3% [CI, 3.0% to 13.6%]) when coadministered with testosterone to men; other performance measures did not significantly change. The increase in sprint capacity was not maintained 6 weeks after discontinuation of the drug. LIMITATIONS: Growth hormone dosage may have been lower than that used covertly by competitive athletes. The athletic significance of the observed improvements in sprint capacity is unclear, and the study was too small to draw conclusions about safety. CONCLUSION: Growth hormone supplementation influenced body composition and increased sprint capacity when administered alone and in combination with testosterone. PRIMARY FUNDING SOURCE: The World Anti-Doping Agency.
Assuntos
Androgênios/farmacologia , Desempenho Atlético/fisiologia , Composição Corporal/efeitos dos fármacos , Hormônio do Crescimento Humano/farmacologia , Testosterona/farmacologia , Tecido Adiposo/efeitos dos fármacos , Adolescente , Adulto , Androgênios/efeitos adversos , Índice de Massa Corporal , Água Corporal/efeitos dos fármacos , Líquido Extracelular/efeitos dos fármacos , Feminino , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Testosterona/efeitos adversos , Adulto JovemRESUMO
CONTEXT: Parafibromin, encoded by HRPT2, is the first marker with significant benefit in the diagnosis of parathyroid carcinoma. However, because parafibromin is only involved in up to 70% of parathyroid carcinomas and loss of parafibromin immunoreactivity may not be observed in all cases of HRPT2 mutation, a complementary marker is needed. OBJECTIVE: We sought to determine the efficacy of increased expression of protein gene product 9.5 (PGP9.5), encoded by ubiquitin carboxyl-terminal esterase L1 (UCHL1) as an additional marker to loss of parafibromin immunoreactivity for the diagnosis of parathyroid carcinoma. DESIGN: In total, 146 parathyroid tumors and nine normal tissues were analyzed for the expression of parafibromin and PGP9.5 by immunohistochemistry and for UCHL1 by quantitative RT-PCR. These samples included six hyperparathyroidism-jaw tumor syndrome-related tumors and 24 sporadic carcinomas. RESULTS: In tumors with evidence of malignancy, strong staining for PGP9.5 had a sensitivity of 78% for the detection of parathyroid carcinoma and/or HRPT2 mutation and a specificity of 100%. Complete lack of nuclear parafibromin staining had a sensitivity of 67% and a specificity of 100%. PGP9.5 was positive in a tumor with the HRPT2 mutation L64P that expressed parafibromin. Furthermore, UCHL1 was highly expressed in the carcinoma/hyperparathyroidism-jaw tumor syndrome group compared to normal (P < 0.05) and benign specimens (P < 0.001). CONCLUSION: These results suggest that positive staining for PGP9.5 has utility as a marker for parathyroid malignancy, with a slightly superior sensitivity (P = 0.03) and similar high specificity to that of parafibromin.
Assuntos
Carcinoma/diagnóstico , Neoplasias das Paratireoides/diagnóstico , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica/métodos , Modelos Biológicos , Mutação/fisiologia , Estadiamento de Neoplasias , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/metabolismo , Neoplasias das Paratireoides/patologia , Sensibilidade e Especificidade , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/análise , Ubiquitina Tiolesterase/genéticaRESUMO
The National Breast and Ovarian Cancer Centre position statement: 'Population screening and early detection of ovarian cancer in asymptomatic women', was developed and agreed following a Forum in February 2009 attended by key Australian stakeholders. The final position statement and supporting background information have been endorsed by key Australian colleges and agencies. Position statement on population screening and early detection of ovarian cancer in asymptomatic women: 1) There is currently no evidence that any test, including pelvic examination, CA125 or other biomarkers, ultrasound (including transvaginal ultrasound), or combination of tests, results in reduced mortality from ovarian cancer. 2) There is no evidence to support the use of any test, including pelvic examination, CA125 or other biomarkers, ultrasound (including transvaginal ultrasound), or combination of tests, for routine population-based screening for ovarian cancer. 3) Further validation in large clinical trials is required before current or new biomarkers could be recommended for routine use in a population screening setting.
Assuntos
Programas de Rastreamento , Neoplasias Ovarianas/prevenção & controle , Biomarcadores Tumorais , Antígeno Ca-125/sangue , Diagnóstico Precoce , Feminino , Humanos , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/diagnóstico por imagem , UltrassonografiaRESUMO
CONTEXT: IGF axis proteins and collagen peptides are promising markers of GH abuse. OBJECTIVE: Our objective was to investigate whether responses of serum IGF axis and collagen markers to GH differ between men and women, and are influenced by testosterone (T). DESIGN: This was a randomized, double-blind, placebo-controlled study of 8-wk treatment followed by 6-wk washout. SETTING: The study was performed at a clinical research facility. PARTICIPANTS: A total of 96 recreationally trained healthy athletes (63 men, 33 women), aged 18-40 yr, were studied. INTERVENTION: All subjects received GH (2 mg/d sc) or placebo for 8 wk; men also received T (250 mg/wk im) or placebo for 5 wk. MAIN OUTCOME MEASURES: Serum IGF axis proteins (IGF-I, IGF binding protein-3, and acid labile subunit) and collagen peptides (N-terminal propeptide of type I procollagen, C-terminal telopeptide of type I collagen, and N-terminal propeptide of type III procollagen) were measured. RESULTS: GH induced significant increases in IGF axis and collagen markers that were greater in men than women (P < 0.001). Of the IGF axis markers, IGF-I showed the greatest increase. The relative incremental responses of the collagen markers in general were greater than the IGF markers, especially for PIIINP. The collagen markers increased and decreased more slowly with most remaining elevated (P < 0.01) after 6 wk, in comparison to IGF markers, which returned to baseline within 1 wk. Addition of T to GH amplified the response of PIIINP by more than 1.5-fold but did not affect any other marker. T alone did not affect IGF axis markers but modestly increased collagen markers. CONCLUSIONS: These markers of GH abuse are less responsive in women. The increases in collagen markers have a different time course to the IGF markers and extend the window of detection in both sexes. The response of PIIINP is increased by coadministration of T.
Assuntos
Biomarcadores Farmacológicos/metabolismo , Hormônio do Crescimento/farmacocinética , Caracteres Sexuais , Esportes , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Testosterona/farmacologia , Adolescente , Adulto , Biomarcadores Farmacológicos/sangue , Proteínas de Transporte/sangue , Proteínas de Transporte/metabolismo , Colágeno/metabolismo , Método Duplo-Cego , Feminino , Glicoproteínas/sangue , Glicoproteínas/metabolismo , Hormônios Esteroides Gonadais/sangue , Hormônio do Crescimento/administração & dosagem , Hormônio do Crescimento/efeitos adversos , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Placebos , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Testosterona/administração & dosagemRESUMO
BACKGROUND: The utility of insulinlike growth factor (IGF) axis and collagen markers for a growth hormone (GH) doping test in sport depends on their stability and reproducibility. We sought to determine short-term within-subject variability of these markers in a large cohort of healthy individuals. METHODS: We measured IGF-I, IGF binding protein 3 (IGFBP-3), acid labile subunit (ALS), and the collagen markers N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (ICTP), and N-terminal propeptide of type III procollagen (PIIINP) in serum samples obtained on multiple occasions (median 3 per participant) over a 2- to 3-week period from 1103 elite athletes (699 men, 404 women) ages 22.2 (5.2) years [mean (SD)]. We estimated between-subject and within-subject variances by mixed-effects ANOVA. RESULTS: Within-subject variance accounted for 32% to 36% and 4% to 13% of the total variance in IGF markers and collagen markers, respectively. The within-subject CV ranged from 11% to 21% for the IGF axis markers and from 13% to 15% for the collagen markers. The index of individuality for the IGF axis markers was 0.66-0.76, and for the collagen markers, 0.26-0.45. For each marker, individuals with initial extreme measured values tended to regress toward the population mean in subsequent repeated measurements. We developed a Bayesian model to estimate the long-term probable value for each marker. CONCLUSIONS: These results indicate that in healthy individuals the within-subject variability was greater for IGF-I than for the collagen markers, and that where a single measurement is available, it is possible to estimate the long-term probable value of each of the markers by applying the Bayesian approach. Such an application can increase the reliability and decrease the cost of detecting GH doping.
Assuntos
Técnicas de Laboratório Clínico , Colágeno/análise , Dopagem Esportivo/prevenção & controle , Hormônio do Crescimento/sangue , Fator de Crescimento Insulin-Like I/análise , Esportes/normas , Detecção do Abuso de Substâncias , Adulto , Análise de Variância , Biomarcadores/sangue , Técnicas de Laboratório Clínico/métodos , Técnicas de Laboratório Clínico/normas , Estudos de Coortes , Colágeno/sangue , Feminino , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Masculino , Sensibilidade e Especificidade , Detecção do Abuso de Substâncias/métodos , Detecção do Abuso de Substâncias/normasRESUMO
Although doping with growth hormone (GH) is banned, there is anecdotal evidence that it is widely abused. GH is reportedly used often in combination with anabolic steroids at high doses for several months. Development of a robust test for GH has been challenging because recombinant human 22 kDa (22K) GH used in doping is indistinguishable analytically from endogenous GH and there are wide physiological fluctuations in circulating GH concentrations. One approach to GH testing is based on measurement of different circulating GH isoforms using immunoassays that differentiate between 22K and other GH isoforms. Administration of 22K GH results in a change in its abundance relative to other endogenous pituitary GH isoforms. The differential isoform method has been implemented; however, its utility is limited because of the short window of opportunity of detection. The second approach, which will extend the window of opportunity of detection, is based on the detection of increased levels of circulating GH-responsive proteins, such as insulin-like growth factor (IGF) axis and collagen peptides. Age and gender are the major determinants of variability for IGF-I and the collagen markers; therefore, a test based on these markers must take age into account for men and women. Extensive data is now available that validates the GH-responsive marker approach and implementation is now largely dependent on establishing an assured supply of standardized assays. Future directions will include more widespread implementation of both approaches by the World Anti-Doping Agency, possible use of other platforms for measurement and an athlete's passport to establish individual reference levels for biological parameters such as GH-responsive markers. Novel approaches include gene expression and proteomic profiling.
Assuntos
Dopagem Esportivo , Hormônio do Crescimento/administração & dosagem , Detecção do Abuso de Substâncias/métodos , HumanosRESUMO
Parathyroid tumors are heterogeneous, and diagnosis is often difficult using histologic and clinical features. We have undertaken expression profiling of 53 hereditary and sporadic parathyroid tumors to better define the molecular genetics of parathyroid tumors. A class discovery approach identified three distinct groups: (1) predominantly hyperplasia cluster, (2) HRPT2/carcinoma cluster consisting of sporadic carcinomas and benign and malignant tumors from Hyperparathyroidism-Jaw Tumor Syndrome patients, and (3) adenoma cluster consisting mainly of primary adenoma and MEN 1 tumors. Gene sets able to distinguish between the groups were identified and may serve as diagnostic biomarkers. We demonstrated, by both gene and protein expression, that Histone 1 Family 2, amyloid beta precursor protein, and E-cadherin are useful markers for parathyroid carcinoma and suggest that the presence of a HRPT2 mutation, whether germ-line or somatic, strongly influences the expression pattern of these 3 genes. Cluster 2, characterized by HRPT2 mutations, was the most striking, suggesting that parathyroid tumors with somatic HRPT2 mutation or tumors developing on a background of germ-line HRPT2 mutation follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumors. Furthermore, our findings likely preclude an adenoma to carcinoma progression model for parathyroid tumorigenesis outside of the presence of either a germ-line or somatic HRPT2 mutation. These findings provide insights into the molecular pathways involved in parathyroid tumorigenesis and will contribute to a better understanding, diagnosis, and treatment of parathyroid tumors.
Assuntos
Neoplasias das Paratireoides/classificação , Neoplasias das Paratireoides/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Família Multigênica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias das Paratireoides/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas/genética , Regulação para CimaRESUMO
OBJECTIVE: To compare estimates by bioimpedance spectroscopy analysis (BIS) of extracellular water (ECW), fat mass (FM), and fat-free mass (FFM) against standard techniques of bromide dilution and dual energy X-ray absorptiometry (DXA) during intervention that causes significant changes in water compartments and body composition. METHODS: Body composition analysis using BIS, bromide dilution, and DXA was performed in 71 healthy recreational athletes (43 men, 28 women; aged 18-40 years; BMI 24 ± 0.4 kg/m(2)) who participated in a double-blinded, randomized, placebo-controlled study of GH and testosterone treatment. The comparison of BIS with bromide dilution and DXA was analyzed using linear regression and the Bland-Altman method. RESULTS: At baseline, there was a significant correlation between BIS and bromide dilution-derived estimates for ECW, and DXA for FM and FFM (P<0.001). ECW by BIS was 3.5 ± 8.1% lower compared with bromide dilution, while FM was 22.4 ± 26.8% lower and FFM 13.7 ± 7.5% higher compared with DXA (P<0.01). During treatment, the change in ECW was similar between BIS and bromide dilution, whereas BIS gave a significantly greater reduction in FM (19.4 ± 44.8%) and a greater increase in FFM (5.6 ± 3.0%) compared with DXA (P<0.01). Significant differences in body composition estimates between the BIS and DXA were observed only in men, particularly during the treatment that caused greatest change in water compartments and body composition. CONCLUSION: In healthy adults, bioimpedance spectroscopy is an acceptable tool for measuring ECW; however, BIS overestimates FFM and substantially underestimates FM compared with DXA.
Assuntos
Absorciometria de Fóton/normas , Composição Corporal/fisiologia , Brometos/sangue , Espectroscopia Dielétrica/normas , Hormônio do Crescimento Humano/uso terapêutico , Absorciometria de Fóton/métodos , Adolescente , Adulto , Espectroscopia Dielétrica/métodos , Método Duplo-Cego , Feminino , Humanos , Masculino , Resultado do Tratamento , Adulto JovemRESUMO
The phosphate-wasting condition, oncogenic osteomalacia, is problematic to diagnose and manage clinically due to difficulty in locating the causative tumor. Fibroblast growth factor 23 (FGF23) has recently been implicated in the pathogenesis of oncogenic osteomalacia. In this case the patient presented with clinical features typical of oncogenic osteomalacia. Removal of an angiolipoma from the thigh did not correct the clinical or biochemical abnormalities. Subsequent identification and removal of a benign giant cell tumor in the pubic ramus, however, did result in normalization of his symptoms and signs. Positive staining for FGF23 protein by immunohistochemistry was demonstrated in the giant cell tumor, but not in the angiolipoma. The serum concentration of FGF23 was elevated in preoperative serum, then normalized after removal of the giant cell tumor. Expression of both FGF23 mRNA and protein was demonstrated in the giant cell tumor tissue, and FGF23 mRNA expression and renal phosphate uptake inhibitory activity were also detected in cultured giant cell tumor cells. This case provides further evidence for the involvement of FGF23 in the pathogenesis of oncogenic osteomalacia and for the utility of serum FGF23 measurement and immunohistochemical detection of FGF23 in the diagnosis and clinical management of this condition.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias/complicações , Osteomalacia/etiologia , Osteomalacia/metabolismo , Biomarcadores , Western Blotting , Neoplasias Ósseas/complicações , Neoplasias Ósseas/patologia , Ensaio de Imunoadsorção Enzimática , Fator de Crescimento de Fibroblastos 23 , Hemangiopericitoma/complicações , Hemangiopericitoma/patologia , Humanos , Imuno-Histoquímica , Rim/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osteomalacia/diagnóstico , Fosfatos/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
The identification of FGF23 as a factor involved in several disorders of phosphate regulation and of PHEX as the gene mutated in X-linked Hypophosphatemic Rickets indicates that both these genes may be involved in phosphate homeostasis, although their physiological roles are unclear. In this study, FGF23 mRNA expression was analyzed by real-time RT-PCR and found to be higher in normal human bone than in kidney, liver, thyroid, or parathyroid tissue, while expression in oncogenic osteomalacia tumor tissue was several hundred-fold higher than in bone. Expression of FGF23 mRNA in human osteoblast-like bone cells, quantitated by real-time RT-PCR, increased with increasing extracellular phosphate and was 2-fold higher in cells treated with 2 mM extracellular phosphate compared to 0 mM phosphate treatment. PHEX mRNA expression increased 1.3-fold after treatment with 2 mM phosphate. FGF23 expression in the bone cells increased with increased mineralization over a 20-day treatment period under mineralizing conditions with beta-glycerophosphate, while PHEX expression decreased. The results indicate that FGF23 mRNA expression in bone cells is regulated by extracellular phosphate and by mineralization. These results support proposals that bone may be a source of circulating FGF23 and suggest that FGF23 expression by bone is regulated.
Assuntos
Osso e Ossos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fosfatos/fisiologia , Calcificação Fisiológica/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Dexametasona/farmacologia , Feto/citologia , Fator de Crescimento de Fibroblastos 23 , Expressão Gênica/efeitos dos fármacos , Glicerofosfatos/farmacologia , Humanos , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteomalacia/metabolismo , Endopeptidase Neutra Reguladora de Fosfato PHEX , Fosfatos/farmacologia , Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The N-terminal regions of 1-34 parathyroid hormone (PTH) and 1-34 parathyroid hormone related protein (PTHrP) are thought to be required for full agonist activity of these molecules and for signal transduction by cyclic AMP (cAMP). The C-terminal regions are thought to be involved in receptor binding and protein kinase C activation. In this study, two analogs of PTH/PTHrP lacking the segment 1-14 exhibited agonist activity in opossum kidney (OK) 3B2 cells. Analogs cPTHrP(15-34) and ANA NPY(13-36), an analog of neuropeptide Y, which both have amphipathic alpha helices, inhibited phosphate uptake and stimulated cAMP production in a dose-dependent manner, with half maximal activity in the microM range, compared to the nM range for hPTHrP(1-34) and hPTH(1-34). They also exhibited proportionately lower receptor binding affinities. cAMP production by these analogs was suppressed by the antagonist hPTHrP(7-34). Inhibition of phosphate uptake in response to the analogs was partially suppressed by H-89, but not by bisindolylmaleimide. The analogs also inhibited phosphate uptake and stimulated cAMP in parent OK cells and stimulated cAMP production in UMR-106 cells. These studies present the novel finding that in these cell types, a C-terminal region encompassing PTH/PTHrP(24-31), with the alpha-helical structure maintained, is sufficient for full activity at reduced potency.
Assuntos
Hormônio Paratireóideo/metabolismo , Hormônios Peptídicos/metabolismo , Sequência de Aminoácidos , Linhagem Celular , AMP Cíclico/análogos & derivados , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Humanos , Dados de Sequência Molecular , Hormônio Paratireóideo/química , Hormônio Paratireóideo/genética , Proteína Relacionada ao Hormônio Paratireóideo , Hormônios Peptídicos/química , Hormônios Peptídicos/genética , Peptídeos/genética , Peptídeos/metabolismo , Fosfatos/metabolismo , Proteína Quinase C/antagonistas & inibidores , Radioimunoensaio , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Doping with growth hormone (GH) is banned; however, there is anecdotal evidence that it is widely abused. GH is reportedly often used in combination with anabolic steroids at high doses for several months. Development of a robust test for detecting GH has been challenging since recombinant human 22-kDa GH used in doping is indistinguishable analytically from endogenous GH and there are wide physiological fluctuations in circulating GH concentrations. DISCUSSION: One approach to GH testing is based on measurement of different circulating GH isoforms using immunoassays that differentiate between 22-kDa and other GH isoforms. Administration of 22-kDa GH results in a change in its abundance relative to other endogenous pituitary GH isoforms. The differential isoform method is, however, limited by its short time window of detection. A second approach that extends the time window of detection is based on detection of increased levels of circulating GH-responsive proteins, such as the insulin-like growth factor (IGF) axis and collagen peptides. As age and gender are the major determinants of variability for IGF-I and the collagen markers, a test based on these markers must take these factors into account. Extensive data now validate the GH-responsive marker approach, and implementation is largely dependent on establishing an assured supply of standardized assays. CONCLUSIONS: Robust tests are available to detect GH and enforce the ban on its abuse in sports. Novel approaches that include gene expression and proteomic profiling must continue to be pursued to expand the repertoire of testing approaches available and to maintain deterrence of GH doping.
Assuntos
Dopagem Esportivo , Hormônio do Crescimento Humano/sangue , Fragmentos de Peptídeos/análise , Isoformas de Proteínas/sangue , Proteínas Recombinantes/sangue , Detecção do Abuso de Substâncias/métodos , Fatores Etários , Anticorpos Monoclonais , Colágeno Tipo I/sangue , Dopagem Esportivo/métodos , Dopagem Esportivo/prevenção & controle , Feminino , Hormônio do Crescimento Humano/análise , Hormônio do Crescimento Humano/urina , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Fragmentos de Peptídeos/sangue , Peptídeos/sangue , Proteômica/métodosRESUMO
There has been limited research and evidence that GH enhances physical performance in healthy adults or in trained athletes. Even so, human growth hormone (GH) is widely abused by athletes. In healthy adults, GH increases lean body mass, although it is possible that fluid retention contributes to this effect. The most recent data indicate that GH does not enhance muscle strength, power, or aerobic exercise capacity, but improves anaerobic exercise capacity. In fact, there are adverse effects of long-term GH excess such that sustained abuse of GH can lead to a state mimicking acromegaly, a condition with increased morbidity and mortality. This review will examine GH effects on body composition and physical performance in health and disease.
Assuntos
Hormônio do Crescimento Humano/fisiologia , Aptidão Física/fisiologia , Acromegalia/induzido quimicamente , Adulto , Anabolizantes/efeitos adversos , Atletas , Composição Corporal/efeitos dos fármacos , Dopagem Esportivo , Sinergismo Farmacológico , Exercício Físico/fisiologia , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Proteínas/metabolismo , Transtornos Relacionados ao Uso de SubstânciasRESUMO
PURPOSE: To determine if time to diagnosis is associated with stage of disease at diagnosis or survival among women with symptomatic ovarian cancer. METHODS: A representative sample of Australian women (n = 1,463) with ovarian cancer diagnosed between 2002 and 2005 who participated in a population-based case-control study were interviewed regarding the events leading to their diagnosis and were observed for mortality for 5 years. RESULTS: Of the 1,318 women (90%) who presented to a medical practitioner with symptoms, 55% presented within 1 month, 70% in less than 2 months, and 92% within 6 months of symptom onset. There were no significant differences in the time from symptom onset to first medical practitioner consultation (P = .19) or symptom onset to diagnosis (P = .64) among women with borderline, early (International Federation of Gynecology and Obstetrics [FIGO] stages I to II) or late (FIGO stages III to IV) disease. There was also no association between time to diagnosis and survival; adjusted hazard ratio for long delay (> 12 months from symptom onset to diagnosis) versus short delay (≤ 1 month) was 0.94 (95% CI, 0.68 to 1.30). Women who had asymptomatic cancers diagnosed incidentally (n = 145) were younger and were more likely to have borderline or stage I disease compared with women who had symptomatic ovarian cancer. CONCLUSION: The results of this study suggest that, once ovarian cancer is symptomatic, reducing the time to diagnosis would not greatly alter stage of disease at diagnosis or survival.
Assuntos
Detecção Precoce de Câncer , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Austrália , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Numerous studies have shown that the majority of women overestimate both their own risk and the populations' risk of developing breast cancer. A number of factors have been found to correlate with perceived risk. METHODS: This paper reports on a telephone survey of a nationally representative sample of approximately 3,000 Australian women aged 30 to 69 years, conducted in 2007, and compares the findings with those of a similar survey conducted in 2003. RESULTS: There was a clear tendency for respondents to overestimate the proportion of women who will develop breast cancer during their lifetime. Approximately half the respondents perceived themselves as being at the same risk of developing breast cancer as other women their age; older respondents were more likely to perceive themselves to be at a lower than average risk. Family history was recognized as a risk factor for breast cancer, although there was evident confusion in relation to risk from paternal family history. It was also evident that the association between age and risk status is poorly understood, and misconceptions of breast cancer risk factors identified in the previous survey persisted in 2007. CONCLUSION: Overall, these results suggest that there remains an educational challenge if we seek to increase the accuracy of women's perceptions of their risk for developing breast cancer, primarily in relation to the significance of age and family history as breast cancer risk factors.
Assuntos
Neoplasias da Mama , Família , Conhecimentos, Atitudes e Prática em Saúde , Adulto , Fatores Etários , Idoso , Austrália , Coleta de Dados , Feminino , Humanos , Pessoa de Meia-Idade , Percepção , Risco , Fatores de RiscoRESUMO
Human growth hormone (GH) is widely abused by athletes; however, there is little evidence that GH improves physical performance. Replacement of GH in GH deficiency improves some aspects of exercise capacity. There is evidence for a protein anabolic effect of GH in healthy adults and for increased lean body mass following GH, although fluid retention likely contributes to this increase. The evidence suggests that muscle strength, power, and aerobic exercise capacity are not enhanced by GH administration, however GH may improve anaerobic exercise capacity. There are risks of adverse effects of long-term abuse of GH. Sustained abuse of GH may lead to a state mimicking acromegaly, a condition with increased morbidity and mortality.
Assuntos
Desempenho Atlético , Dopagem Esportivo/legislação & jurisprudência , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Adulto , Aerobiose , Anaerobiose , Composição Corporal , Exercício Físico/fisiologia , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Força Muscular , Consumo de Oxigênio , Proteínas/metabolismo , Fatores de RiscoRESUMO
OBJECTIVE: To describe the diagnostic pathways experienced by a large, representative group of Australian women with ovarian cancer, and to document the time between first presentation to a medical professional and clinical diagnosis. DESIGN, SETTING AND PARTICIPANTS: 1463 women with epithelial ovarian cancer from an Australia-wide population-based study (2002-2005) completed a telephone interview in which they described the events that led to the diagnosis of their cancer. MAIN OUTCOME MEASURES: Number and type of doctors consulted, investigations performed, referral patterns and the time from first presentation to diagnosis. RESULTS: Of the 1463 women, 145 had their cancer diagnosed incidentally and were excluded from analysis. Most of the remaining 1318 women (1222, 93%) presented first to their general practitioner. As a result of their first medical consultation, 75 women (6%) were given a diagnosis, and 484 (37%) were referred to a gynaecologist, gynaecological oncologist or oncologist for further assessment. Overall, 85% of women visited three or fewer doctors before their cancer was diagnosed; 66% of cancers were diagnosed within 1 month of the initial presentation, and 80% were diagnosed within 3 months. For 12% of women, the diagnostic process took longer than 6 months; this was more likely for women residing in remote Australia, those with lower incomes, and those presenting with abdominal pain or bowel symptoms, or with more than one symptom. CONCLUSIONS: Despite anecdotal suggestions to the contrary, most women with ovarian cancer in Australia are investigated and diagnosed promptly. The diagnostic process is more protracted for a minority of women, and the factors we found to be associated with diagnostic delay warrant further investigation.
Assuntos
Neoplasias Ovarianas/diagnóstico , Encaminhamento e Consulta/organização & administração , Idoso , Austrália , Intervalos de Confiança , Diagnóstico Tardio , Feminino , Disparidades nos Níveis de Saúde , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Grupos Minoritários , Razão de Chances , Neoplasias Ovarianas/etnologia , Encaminhamento e Consulta/estatística & dados numéricosRESUMO
Application of methods for detecting GH doping depend on being able to discriminate between abnormal levels due to doping and normal physiological levels of circulating proteins that change in response to exogenous administration. Constituents of the IGF and collagen systems have been shown to be promising markers of GH abuse. Their ultimate utility, however, depends on identification of the factors that regulate their concentrations in blood. Among these are demographic factors that are known to influence these markers in the general population. In a large cross-sectional study of the GH-responsive markers in over 1000 elite athletes from 12 countries representing 4 major ethnic groups and 10 sport types, we have shown that there is a significant negative correlation between age and all the IGF and collagen markers we studied, with a rapid decrease in early adolescence. Age was the major contribution to the variability, equivalent to >80% of the attributable variation in IGF-I and the collagen markers. The IGF axis markers were all significantly higher in women, and the collagen markers significantly higher in men, however, the contribution of gender was smaller than that of age, except for IGFBP-3 and ALS. BMI had a minor contribution to variability of the GH-responsive markers. After adjustment for the confounding influences of age, gender and BMI, the effect of ethnicity in elite athletes was trivial except for IGFBP-3 and ALS, which were both lower in Africans and higher in Caucasians. Compared to age and gender, the contribution of sport type was also modest. Our findings on the influence of age, gender, BMI and sport type have also been confirmed in a study of mostly Caucasian elite athletes in the post-competition setting. In conclusion, age and gender are the major determinants of variability for IGF-I and the collagen markers, whereas ethnicity and sport type have a minor influence. Therefore, a test based on IGF-I and the collagen markers must take age into account for men and women, and ethnicity and sport type are unlikely to be confounders for these markers.