RESUMO
This prospective study investigated the functional recovery of surgically treated dogs with thoracolumbar intervertebral disc extrusion (IVDE) without deep pain perception (DPP) for > 96 h. Dogs (n = 36) with paraplegia secondary to thoracolumbar intervertebral disc extrusion with loss of deep pain perception ranging from 4 to 60 days were enrolled. All dogs underwent hemilaminectomy and fenestration of the affected intervertebral disc and postoperative follow-up was provided for a maximum of 180 days. Recovery of motor function was satisfactory (based on the owner's assessment) in 22 dogs, 61.1% (47.2% with DPP, and 13.9% without DPP) and unsatisfactory in 38.9% of cases (n = 14). Postoperative physiotherapy, preoperative anti-inflammatory drugs, and age had no effect on recovery. In this study, the longer the time taken to regain pain perception, the longer the recovery time. The median time to recovery was 30 days. A total of 47.2% of dogs with paraplegia and absence of DPP secondary to thoracolumbar IVDE lasting > 96 h, recovered functional ambulation after decompressive surgery.
RESUMO
O objetivo deste trabalho foi verificar em quais projeções foi possível identificar compressão da medula espinhal em cães com doença do disco intervertebral (DDIV) cervical e propor um sequenciamento das projeções a ser realizado no exame mielográfico dessa região. Foram avaliadas quatro projeções mielográficas (lateral, ventrodorsal e oblíquas esquerda e direita) de 41 pacientes diagnosticados com DDIV cervical. Em 40 pacientes (97,5%), foi possível identificar compressão da medula espinhal na projeção lateral; em 22 (53,6%), nas oblíquas; e em 11 (26,8%), na ventrodorsal (P<0,05). Havia lateralização da compressão em 22 (53,6%) pacientes; 100% delas (n=22) foram detectadas pelas projeções oblíquas e 50% (n=11) pela ventrodorsal. Em 10 (24,4%) cães, foi observado mais que um local de compressão, tendo as projeções ventrodorsal e oblíquas auxiliado na definição do local de compressão em 50% e 70%, respectivamente. Pode-se concluir que todas as projeções mielográficas estudadas permitem identificar compressão na medula espinhal em cães com DDIV cervical, sendo a incidência lateral a que mais a revelou, seguida das oblíquas e da ventrodorsal, estabelecendo-se, assim, uma proposta de sequenciamento das projeções mielográficas a serem realizadas para essa região.(AU)
The aim of this study was to verify in which of the myelographic views it was possible to identify spinal cord compression in dogs with cervical intervertebral disc disease (IVDD), and to establish a sequence in which myelographic views should be obtained for this region. Four myelographic views (lateral, ventrodorsal, left oblique and right oblique) of 41 patients diagnosed with cervical IVDD were evaluated. In 40 patients (97.5%) it was possible to identify spinal cord compression by lateral view, 22 (53.6%) by the oblique view, and 11 (26.8%) by the ventrodorsal view (P< 0.05). There were lateralized compressions in 22 (53.6%) patients, detected by all oblique views (100%) and by 11 (50%) of the ventrodorsal views. In 10 (24.4%) dogs, more than one compression site was observed, where the ventrodorsal view helped to decide the site in 50% of the cases and oblique in 70%. It can be concluded that all the tested myelographic views allow the identification of spinal cord compressions in dogs with cervical IVDD, the lateral view being the most relevant, followed by the oblique and ventrodorsal view, therefore establishing a sequence of myelographic views should be obtained for this region.(AU)
Assuntos
Animais , Cães , Compressão da Medula Espinal/diagnóstico por imagem , Disco Intervertebral/patologia , Mielografia/veterináriaRESUMO
Systemic inflammation is associated with arteriosclerotic disease progression and worse stroke outcome in patients with carotid arteriosclerotic disease. We hypothesize that systemic inflammation is mediated by impaired carotid baroreceptor and chemoreceptor function induced by carotid arteriosclerosis rather than by the generalized inflammatory arteriosclerotic process.Heart rate variability (HRV), serum levels of inflammatory markers, demographic and life style factors, and concomitant diseases with potential impact on systemic inflammation were determined in 105 patients with asymptomatic carotid stenosis of varying degree. Multivariate linear regression analyses were performed to ascertain independent determinants of carotid stenosis severity, autonomic function, and inflammation.Systemic inflammation (C-reactive protein, beta = .255; P = .014), age (beta = .232; P < .008), and arterial hypertension (beta = .206; P = .032) were associated with carotid stenosis severity. Only carotid stenosis severity and not generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia, hypothyroidism), life style factors (smoking, obesity), or age was associated with a reduction in vagal tone (HRV HF band power beta = - .193; P < 0.049). Systemic inflammation was related to a reduction in vagal tone (HRV HF band power, beta = - .214; P = .031), and not to generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia), life style factors (smoking, obesity), and age.In conclusion, systemic inflammation is associated with carotid rather than with generalized arteriosclerotic disease. The association between systemic inflammation and carotid arteriosclerosis is mediated by a reduction in vagal tone which indicates a major role of carotid arteriosclerosis-mediated autonomic dysfunction in the pathogenesis of systemic inflammation in arteriosclerotic disease.
Assuntos
Arteriosclerose/complicações , Doenças do Sistema Nervoso Autônomo/complicações , Estenose das Carótidas/complicações , Inflamação/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Arteriosclerose/sangue , Doenças do Sistema Nervoso Autônomo/sangue , Estenose das Carótidas/sangue , Feminino , Frequência Cardíaca , Humanos , Inflamação/sangue , Estilo de Vida , Masculino , Pessoa de Meia-IdadeRESUMO
Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.
Assuntos
Antivirais/administração & dosagem , Ácidos e Sais Biliares/sangue , Lipopeptídeos/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir/farmacocinética , Administração Oral , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Biomarcadores/sangue , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Feminino , Humanos , Injeções Subcutâneas , Lipopeptídeos/efeitos adversos , Lipopeptídeos/farmacocinética , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Estudos Prospectivos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Medição de Risco , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Regulação para Cima , Adulto JovemRESUMO
Este estudo retrospectivo teve como objetivo demonstrar as modalidades fisioterapêuticas empregadas no tratamento de cães com doença do disco intervertebral (DDIV) toracolombar após descompressão cirúrgica da medula espinhal, bem como relatar os fatores que determinaram as alterações das modalidades. Foram incluídos 30 cães que apresentavam sinais neurológicos desde paraparesia ambulatória a paraplegia com dor profunda na primeira sessão de fisioterapia. As modalidades utilizadas nos protocolos de todos os pacientes foram a crioterapia, massagem, alongamento passivo, movimentação passiva articular, estímulo do reflexo flexor e estimulação elétrica neuromuscular. A inclusão ou exclusão de exercícios terapêuticos, como a tipoia corporal, a plataforma proprioceptiva circular, a natação, a hidroesteira, os obstáculos e a caminhada em colchão, foi de acordo com a evolução clínica e a adaptação de cada paciente. Oitenta por cento (80%) dos cães alteraram o grau de disfunção neurológica antes de iniciar a fisioterapia e 93% retornaram à habilidade de caminhar (paraparesia ambulatória) ao final da fisioterapia. O número de sessões e o tempo de recuperação foram maiores quanto pior foi o grau de lesão do paciente.(AU)
This retrospective study aimed to demonstrate the physiotherapeutic modalities used in the treatment of dogs with thoracolumbar intervertebral disc disease (IVDD) after surgical spinal cord decompression and to report elements that determined the modalities changes. Thirty dogs with deep pain perception were selected in the first physiotherapy session, presenting a range of clinical signs from ambulatory paraparesis to paraplegia. The modalities used in the protocols of all patients were cryotherapy, massage, passive stretching, passive range of motion, flexor reflex stimulation and neuromuscular electrical stimulation. The inclusion or exclusion of the therapeutic exercises how body sling (walking sling), circular proprioceptive platform, swimming, underwater treadmill, cavaletti rails and foam mattress walking were according to the clinical evolution and acceptance of each patient. Eighty percent (80%) of the dogs manifested improvement in their neurological dysfunction degree before starting physical therapy and 93% were able to walk again (ambulatory paraparesis) at the end of physiotherapy. The number of sessions and recovery times were higher in patients with higher neurological dysfunction degrees.(AU)
Assuntos
Animais , Cães , Cães/cirurgia , Disco Intervertebral/fisiopatologia , Reabilitação , Especialidade de FisioterapiaRESUMO
Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including the TPMT gene region, were significantly associated with TPMT activity (P < 5.0 × 10-8 ) in each of the three GWAS and a joint meta-analysis of 1,212 cases (top hit P = 1.2 × 10-72 ). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize mercaptopurine dosage.
Assuntos
Estudo de Associação Genômica Ampla , Metiltransferases/genética , Polimorfismo Genético/genética , Alelos , Estônia , Humanos , FenótipoAssuntos
Citocromo P-450 CYP2D6/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Testes Genéticos/métodos , Ondansetron/farmacologia , Náusea e Vômito Pós-Operatórios/prevenção & controle , Tropizetrona/farmacologia , Antieméticos/farmacologia , Humanos , Farmacogenética/métodos , Polimorfismo Genético , Radioterapia/efeitos adversos , Agonistas do Receptor 5-HT3 de Serotonina/farmacologiaRESUMO
Why does a microwave oven work? How does biological tissue absorb electromagnetic radiation? Astonishingly, we do not have a definite answer to these simple questions because the microscopic processes governing the absorption of electromagnetic waves by water are largely unclarified. This absorption can be quantified by dielectric loss spectra, which reveal a huge peak at a frequency of the exciting electric field of about 20 GHz and a gradual tailing off toward higher frequencies. The microscopic interpretation of such spectra is highly controversial and various superpositions of relaxation and resonance processes ascribed to single-molecule or molecule-cluster motions have been proposed for their analysis. By combining dielectric, microwave, THz, and far-infrared spectroscopy, here we provide nearly continuous temperature-dependent broadband spectra of water. Moreover, we find that corresponding spectra for aqueous solutions reveal the same features as pure water. However, in contrast to the latter, crystallization in these solutions can be avoided by supercooling. As different spectral contributions tend to disentangle at low temperatures, this enables us to deconvolute them when approaching the glass transition under cooling. We find that the overall spectral development, including the 20 GHz feature (employed for microwave heating), closely resembles the behavior known for common supercooled liquids. Thus water's absorption of electromagnetic waves at room temperature is not unusual but very similar to that of glass-forming liquids at elevated temperatures, deep in the low-viscosity liquid regime, and should be interpreted along similar lines.
RESUMO
Heritability of caffeine pharmacokinetics and cytochrome P450 1A2 (CYP1A2) activity is controversial. Here, we analyzed the pharmacokinetics of caffeine, an in vivo probe drug for CYP1A2 and arylamine N-acetyltransferase 2 (NAT2) activity, in monozygotic (MZ) and dizygotic (DZ) twins. In the entire group, common and unique environmental effects explained most variation in caffeine area under the curve (AUC). Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity. However, when excluding smokers and users of hormonal contraceptives, 89% of caffeine AUC variation was due to genetic effects and, even in the entire group, 8% of caffeine AUC variation could be explained by a CYP1A1/1A2 promotor polymorphism (rs2470893). In contrast, nearly all of the variations (99%) of NAT2 activity were explained by genetic effects. This study illustrates two very different situations in pharmacogenetics from an almost exclusively genetic determination of NAT2 activity with no environmental modulation to only moderate genetic effects on CYP1A2 activity with strong environmental modulation.
Assuntos
Arilamina N-Acetiltransferase/genética , Cafeína/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Farmacogenética , Adolescente , Adulto , Área Sob a Curva , Anticoncepcionais Orais Hormonais/administração & dosagem , Meio Ambiente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fumar/metabolismo , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto JovemRESUMO
Multidrug resistance protein 8 (ABCC11) is an efflux transporter for anionic lipophilic compounds, conferring resistance to antiviral and anticancer agents like 5-fluorouracil (5-FU). ABCC11 missense variants may contribute to variability in drug response but functional consequences, except for the 'earwax variant' c.538G>A, are unknown. Using the 'Screen and Insert' technology, we generated human embryonic kidney 293 cells stably expressing ABCC11 missense variants frequently occurring in different ethnic populations: c.57G>A, c.538G>A, c.950C>A, c.1637C>T, c.1942G>A, c.4032A>G. A series of in silico prediction analyses and in vitro plasma membrane vesicle uptake, immunoblotting and immunolocalization experiments were undertaken to investigate functional consequences. We identified c.1637C>T (T546M), previously associated with 5-FU-related toxicity, as a novel functionally damaging ABCC11 variant exhibiting markedly reduced transport function of 5-FdUMP, the active cytotoxic metabolite of 5-FU. Detailed analysis of 14 subpopulations revealed highest allele frequencies of c.1637C>T in Europeans and Americans (up to 11%) compared with Africans and Asians (up to 3%).
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adenosina Trifosfatases/metabolismo , Antineoplásicos/metabolismo , Povo Asiático , Transporte Biológico , População Negra , Linhagem Celular , Simulação por Computador , Sulfato de Desidroepiandrosterona/metabolismo , Estrona/análogos & derivados , Estrona/metabolismo , Fluordesoxiuridilato/metabolismo , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Mutação de Sentido Incorreto , População BrancaRESUMO
The presence or absence of estrogen and progesterone steroid hormone receptor expression (ER, PR) is an essential feature of invasive breast cancer and determines prognosis and endocrine treatment decisions. Among the four ER/PR receptor phenotypes, the ER-/PR+ is infrequent, and its clinical relevance has been controversially discussed. Thus, we investigated its clinical significance and gene expression pattern in large datasets. In a retrospective clinical study of 15,747 breast cancer patients, we determined the ER/PR subtype survival probabilities using Kaplan-Meier and Cox regression analyses. From The Cancer Genome Atlas (TCGA) breast cancer dataset, PAM50 expression signature and pathway analyses were performed to test for distinct molecular features. In our cohort, the ER-/PR+ phenotype has been observed at a frequency of 4.1 % and was associated with an improved 10-year survival for stage I cancers compared to the ER+/PR+ reference subtype (median; 95 % CI 88.1 %; 83-93 vs. 84.3 %; 82-86 %, P = 0.024) as was confirmed by multivariate analysis over the entire follow-up (HR 0.59, 95 % CI 0.38-0.92, P = 0.021). This association lacked significance when including all stages. ER-/PR+ patients treated with antihormonal agents (34.5 %) had shorter survival compared to their non-treated counterparts (Log-rank P = 0.0001). PAM50 signatures suggest a distinct configuration for the ER-/PR+ phenotype. This specific phenotype has been further separated by a set of 59 uniquely expressed genes. Our study supports the notion of the existence of an ER-/PR+ phenotype with clinical and molecular features distinct from the large group of ER+/PR+ patients.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Perfilação da Expressão Gênica , Fenótipo , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Análise de Sobrevida , Adulto JovemRESUMO
Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated.
Assuntos
Hereditariedade , Metoprolol/farmacocinética , Polimorfismo Genético , Sulfonamidas/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Biotransformação/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Feminino , Genótipo , Humanos , Infusões Intravenosas , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Metoprolol/administração & dosagem , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Farmacogenética , Fenótipo , Sulfonamidas/administração & dosagem , Torasemida , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto JovemRESUMO
BACKGROUND: Platelet secretion is critical to development of acute thrombotic occlusion. Platelet dense granules contain a variety of important hemostatically active substances. Nevertheless, biogenesis of platelet granules is poorly understood. OBJECTIVES: Serum- and glucocorticoid-inducible kinase 1 (SGK1) has been shown to be highly expressed in platelets and megakaryocytes, but its role in the regulation of platelet granule biogenesis and its impact on thrombosis has not been investigated so far. METHODS AND RESULTS: Electron microscopy analysis of the platelet ultrastructure revealed a significant reduction in the number and packing of dense granules in platelets lacking SGK1 (sgk1(-/-) ). In sgk1(-/-) platelets serotonin content was significantly reduced and activation-dependent secretion of ATP, serotonin and CD63 significantly impaired. In vivo adhesion after carotis ligation was significantly decreased in platelets lacking SGK1 and occlusive thrombus formation after FeCl3 -induced vascular injury was significantly diminished in sgk1(-/-) mice. Transcript levels and protein abundance of dense granule biogenesis regulating GTPase Rab27b were significantly reduced in sgk1(-/-) platelets without affecting Rab27b mRNA stability. In MEG-01 cells transfection with constitutively active (S422) (D) SGK1 but not with inactive (K127) (N) SGK1 significantly enhanced Rab27b mRNA levels. Sgk1(-/-) megakaryocytes show significantly reduced expression of Rab27b and serotonin/CD63 levels compared with sgk1(+/+) megakaryocytes. Proteome analysis identified nine further vesicular transport proteins regulated by SGK1, which may have an impact on impaired platelet granule biogenesis in sgk1(-/-) platelets independent of Rab27b. CONCLUSIONS: The present observations identify SGK1 as a novel powerful regulator of platelet dense granule biogenesis, platelet secretion and thrombus formation. SGK1 is at least partially effective because it regulates transcription of Rab27b in megakaryocytes.
Assuntos
Plaquetas/enzimologia , Lesões das Artérias Carótidas/enzimologia , Grânulos Citoplasmáticos/enzimologia , Proteínas Imediatamente Precoces/sangue , Ativação Plaquetária , Proteínas Serina-Treonina Quinases/sangue , Vesículas Secretórias/enzimologia , Trombose/enzimologia , Trifosfato de Adenosina/sangue , Trifosfato de Adenosina/metabolismo , Animais , Plaquetas/metabolismo , Plaquetas/ultraestrutura , Lesões das Artérias Carótidas/sangue , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/patologia , Células Cultivadas , Grânulos Citoplasmáticos/metabolismo , Grânulos Citoplasmáticos/ultraestrutura , Modelos Animais de Doenças , Feminino , Genótipo , Proteínas Imediatamente Precoces/deficiência , Proteínas Imediatamente Precoces/genética , Masculino , Megacariócitos/enzimologia , Megacariócitos/metabolismo , Camundongos Knockout , Fenótipo , Agregação Plaquetária , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/metabolismo , Vesículas Secretórias/metabolismo , Vesículas Secretórias/ultraestrutura , Serotonina/sangue , Serotonina/metabolismo , Transdução de Sinais , Tetraspanina 30/sangue , Tetraspanina 30/metabolismo , Trombose/sangue , Trombose/genética , Trombose/patologia , Fatores de Tempo , Transfecção , Regulação para Cima , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Currently available data on prognostic implication of additional neoplasms in GIST miss comprehensive information on patient outcome with regard to overall or disease specific and disease free survival. Registry data of GIST patients with and without additional neoplasm were compared in retrospective case series. We investigated a total of 836 patients from the multi-center Ulmer GIST registry. Additionally, a second cohort encompassing 143 consecutively recruited patients of a single oncology center were analyzed. The frequency of additional malignant neoplasms in GIST patients was 31.9% and 42.0% in both cohorts with a mean follow-up time of 54 and 65 months (median 48 and 60 months), respectively. The spectrum of additional neoplasms in both cohorts encompasses gastrointestinal tumors (43.5%), uro-genital and breast cancers (34.1%), hematological malignancies (7.3%), skin cancer (7.3%) and others. Additional neoplasms have had a significant impact on patient outcome. The five year overall survival in GIST with additional malignant neoplasms (n = 267) was 62.8% compared to 83.4% in patients without other tumors (n = 569) (P < .001, HR=0.397, 95% CI: 0.298-0.530). Five-year disease specific survival was not different between both groups (90.8% versus 90.9%). 34.2% of all deaths (n = 66 of n = 193) were GIST-related. The presented data suggest a close association between the duration of follow-up and the rate of additional malignancies in GIST patients. Moreover the data indicate a strong impact of additional malignant neoplasms in GIST on patient outcome. A comprehensive follow-up strategy of GIST patients appears to be warranted.
Assuntos
Tumores do Estroma Gastrointestinal/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Tumores do Estroma Gastrointestinal/patologia , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Segunda Neoplasia Primária/diagnóstico , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Sistema de Registros , Análise de Sobrevida , Adulto JovemRESUMO
At present, the global diabetes epidemic is affecting 347 million individuals, 90% of whom are diagnosed with type II diabetes mellitus (T2DM). T2DM is commonly treated with more than one type of therapy, including oral antidiabetic drugs (OADs) and agents used in the treatment of diabetic complications. Several pharmacological classes of OADs are currently available for the treatment of T2DM, of which insulin secretagogues (i.e. sulphonylureas and meglitinides), insulin sensitizers [thiazolidinediones (TZDs)] and biguanides are the most commonly prescribed. Although many of these OADs have been used for more than half a century in the treatment of T2DM, the pharmacogenomic characteristics of these compounds have only recently been investigated, primarily in retrospective studies. Recent advances in pharmacogenomics have led to the identification of polymorphisms that affect the expression and function of drug-metabolizing enzymes and drug transporters, as well as drug targets and receptors. These polymorphisms have been shown to affect the therapeutic response to and side effects associated with OADs. The aim of this review was to provide an up-to-date summary of some of the pharmacogenomic data obtained from studies of T2DM treatment, with a focus on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly prescribed OADs. In addition, the implications of pharmacogenomics in the use of the OAD metformin in cancer will be briefly discussed. Finally, we will focus on recent advances in novel 'omics' technologies and discuss how these might aid in the personalized management of T2DM.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Polimorfismo Genético , Administração Oral , Biguanidas/uso terapêutico , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/epidemiologia , Medicina Baseada em Evidências , Saúde Global , Humanos , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Neoplasias/epidemiologia , Tiazolidinedionas/uso terapêutico , Resultado do TratamentoRESUMO
Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.
Assuntos
Antineoplásicos Hormonais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Detecção Precoce de Câncer , Pré-Menopausa/sangue , Tamoxifeno/sangue , Adulto , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Tamoxifeno/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Nogo-A is a well-known myelin-enriched inhibitory protein for axonal growth and regeneration in the central nervous system (CNS). Besides oligodendrocytes, our previous data revealed that Nogo-A is also expressed in subpopulations of neurons including retinal ganglion cells, in which it can have a positive role in the neuronal growth response after injury, through an unclear mechanism. In the present study, we analyzed the opposite roles of glial versus neuronal Nogo-A in the injured visual system. To this aim, we created oligodendrocyte (Cnp-Cre(+/-)xRtn4/Nogo-A(flox/flox)) and neuron-specific (Thy1-Cre(tg+)xRtn4(flox/flox)) conditional Nogo-A knock-out (KO) mouse lines. Following complete intraorbital optic nerve crush, both spontaneous and inflammation-mediated axonal outgrowth was increased in the optic nerves of the glia-specific Nogo-A KO mice. In contrast, neuron-specific deletion of Nogo-A in a KO mouse line or after acute gene recombination in retinal ganglion cells mediated by adeno-associated virus serotype 2.Cre virus injection in Rtn4(flox/flox) animals decreased axon sprouting in the injured optic nerve. These results therefore show that selective ablation of Nogo-A in oligodendrocytes and myelin in the optic nerve is more effective at enhancing regrowth of injured axons than what has previously been observed in conventional, complete Nogo-A KO mice. Our data also suggest that neuronal Nogo-A in retinal ganglion cells could participate in enhancing axonal sprouting, possibly by cis-interaction with Nogo receptors at the cell membrane that may counteract trans-Nogo-A signaling. We propose that inactivating Nogo-A in glia while preserving neuronal Nogo-A expression may be a successful strategy to promote axonal regeneration in the CNS.
Assuntos
Axônios/fisiologia , Proteínas da Mielina/genética , Traumatismos do Nervo Óptico/terapia , Regeneração , Células Ganglionares da Retina/fisiologia , Transdução de Sinais , Animais , Dependovirus/genética , Feminino , Vetores Genéticos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Bainha de Mielina/fisiologia , Compressão Nervosa , Neuroglia/citologia , Neurônios/citologia , Proteínas NogoRESUMO
BACKGROUND: Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies METHODS: Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test. RESULTS: Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity. CONCLUSIONS: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.