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1.
J Inherit Metab Dis ; 40(4): 555-567, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28643139

RESUMO

Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.


Assuntos
Arginina/química , Cisteamina/química , Cisteína/química , Cistinose/terapia , Mutação , Animais , Apolipoproteína E3/metabolismo , Argininossuccinato Liase/metabolismo , Cistationina beta-Sintase/metabolismo , Cistinose/genética , Cistinose/metabolismo , Homeostase , Humanos , Concentração de Íons de Hidrogênio , Conformação Molecular , Mutação de Sentido Incorreto , Oxirredução , Compostos de Sulfidrila/química , Tromboplastina/metabolismo
2.
Bone Marrow Transplant ; 51(3): 384-90, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26642334

RESUMO

Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty-one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P<0.001 and P=0.032). On multivariable analysis from the model with fully available data (N=216) progression to induction was significantly prognostic for PFS and OS (P=0.003), but prior paclitaxel was not (P=0.674 and P=0.739). These results were confirmed after multiple imputation of missing data. Progression to induction chemotherapy could be demonstrated as an independent prognostic factor, in contrast to prior paclitaxel.


Assuntos
Quimioterapia de Indução , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/terapia , Paclitaxel/administração & dosagem , Terapia de Salvação , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Taxa de Sobrevida , Adulto Jovem
3.
Bone Marrow Transplant ; 49(4): 509-12, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24419513

RESUMO

Previous studies have shown an equivalent pharmacokinetic profile between four-times-daily (4QD) and once-daily (QD) administration of intra-venous (IV) BU, without increased toxicity. We assess the impact of a switch in IV BU from a 4QD to a QD schedule, in terms of health-care organization, staff working conditions, quality of care dispensed and perceived patient comfort. Clinicians, nurses and pharmacists from nine allogeneic transplantation units in five European countries were interviewed face to face. Overall perception of QD versus 4QD BU was very positive. Both administration schemes were evaluated to be equally efficaciousZ. QD BU was perceived to be safer and more convenient. Clinicians and nurses perceived that patient comfort was improved, due to fewer complications associated with repeated infusions, and avoiding night infusions associated with stress, anxiety and decreased quality of sleep. Switching from 4QD to QD BU had a significant impact on health-care organization, with a better integration in the overall management and usual timelines in the pharmacies and transplantation units. Time spent to prepare and administer BU was significantly reduced, leading to potential financial savings that merit further assessment and would be of particular interest in the current economic climate.


Assuntos
Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Satisfação do Paciente , Condicionamento Pré-Transplante/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Atitude do Pessoal de Saúde , Bussulfano/farmacocinética , Atenção à Saúde/métodos , Atenção à Saúde/organização & administração , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo
4.
Br J Cancer ; 109(10): 2523-32, 2013 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-24149176

RESUMO

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported. METHODS: We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months. RESULTS: Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR. CONCLUSION: The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Rabdomiossarcoma/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/mortalidade , Estudos Retrospectivos , Rabdomiossarcoma/mortalidade , Transplante Homólogo , Adulto Jovem
5.
Br J Pharmacol ; 169(6): 1239-51, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23594166

RESUMO

BACKGROUND AND PURPOSE: Albuminuria is an important biomarker of renal dysfunction and is a major mediator of renal damage and fibrosis during kidney disease. The mechanisms underlying albumin-induced renal fibrosis remain unclear. There has been significant interest in γ-secretase activity in tubular epithelial cells in recent times; however, its potential role in albumin-induced fibrosis has not been investigated. EXPERIMENTAL APPROACH: The primary aim of this study was to examine the role of γ-secretase in albumin-induced fibrotic effects in proximal tubular cells. The effects of increasing albumin concentrations on fibrosis indicators and mediators in the human HK-2 cell line were examined in the presence and absence of a γ-secretase inhibitor, compound E. KEY RESULTS: Treatment with albumin resulted in a number of pro-fibrotic effects, including up-regulation of fibronectin, TGF-ß1 and the EGF-R. Interestingly, similar effects were observed in response to treatment with the γ-secretase inhibitor, compound E. Co-treatment of cells with albumin and an EGF-R inhibitor, AG-1478, resulted in significant inhibition of the observed pro-fibrotic effects, suggesting a major role for the EGF-R in albumin-induced fibrotic events. Albumin-induced effects on the EGF-R appeared to be mediated through inhibition of γ-secretase activity and were dependent on ERK-MAPK signalling. CONCLUSIONS AND IMPLICATIONS: These results provide novel insights into the mechanisms of albumin-induced fibrotic effects in tubular epithelial cells, suggesting important roles for the γ-secretase and the EGF-R. These results suggest that the proposed use of γ-secretase inhibitors as anti-fibrotic agents requires further investigation.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Endocitose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Soroalbumina Bovina/metabolismo , Urotélio/efeitos dos fármacos , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Benzodiazepinonas/farmacologia , Bovinos , Linhagem Celular , Meios de Cultura Livres de Soro , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Fibronectinas/metabolismo , Fibrose , Humanos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Gambás , Quinazolinas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Tirfostinas/farmacologia , Urotélio/metabolismo , Urotélio/patologia
6.
Ann Oncol ; 23(4): 823-33, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21948809

RESUMO

Invasive fungal infections (IFIs) are a primary cause of morbidity and mortality in patients with hematological malignancies. Establishing a definite diagnosis of IFI in immunocompromised patients is particularly challenging and time consuming, but delayed initiation of antifungal treatment increases mortality. The limited overall outcome has led to the strategy of initiating either 'empirical' or 'preemptive' antifungal therapy before the final diagnosis. However, diagnostic procedures have been vastly improved in recent years. Particularly noteworthy is the introduction of newer imaging techniques and non-culture methods, including antigen-based assays, metabolite detection and molecular detection of fungal DNA from body fluid samples. Though varying widely in cancer patients, the risk of IFI is highest in those with allogeneic stem cell transplantation and those with acute leukemia. The AGIHO presents recommendations for the diagnosis of IFIs with risk-adapted screening concepts for febrile episodes in patients with haemato-oncological disorders.


Assuntos
Neoplasias Hematológicas/complicações , Pneumopatias Fúngicas/diagnóstico , Infecções Oportunistas/diagnóstico , Hematologia , Humanos , Pneumopatias Fúngicas/complicações , Oncologia , Infecções Oportunistas/complicações
7.
Ann Oncol ; 23(7): 1809-12, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22115927

RESUMO

BACKGROUND: We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. PATIENTS AND METHODS: From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. RESULTS: Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%. CONCLUSIONS: Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of life.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias do Sistema Nervoso Central/terapia , Linfoma/terapia , Metotrexato/administração & dosagem , Transplante de Células-Tronco , Adolescente , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/mortalidade , Terapia Combinada , Irradiação Craniana , Feminino , Seguimentos , Humanos , Avaliação de Estado de Karnofsky , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Transplante Autólogo
10.
Curr Alzheimer Res ; 7(2): 140-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19939226

RESUMO

Hyperhomocysteinemia (HHcy) has been recognized as a risk factor for developing Alzheimer's disease (AD). However, its underlying molecular mechanisms are still elusive. Here we show that HHcy induces an elevation of amyloid beta (Abeta) levels and deposition, as well as behavioral impairments, in a mouse model of AD-like amyloidosis, the Tg2576 mice. This elevation is not associated with significant change of the steady state levels of the Abeta precursor protein (APP), beta- or alpha-secretase pathways, nor with the Abeta catabolic pathways. By contrast, HHcy significantly reduces glycogen synthase kinase 3 (GSK3) Ser21/9 phosphorylation, but not total GSK3 protein levels. Similar results are obtained in brains homogenates from a genetic mouse model of HHcy. In vitro studies show that homocysteine increases Abeta formation, reduces phosphorylated GSK3 levels, without changes in total APP and its metabolism, and these effects are prevented by selective GSK3 inhibition. Overall, these data support a potential link between GSK3 and the pro-amyloidotic effect of HHcy in vivo and in vitro.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Homocisteína/sangue , Hiper-Homocisteinemia/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Sequência de Aminoácidos/fisiologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Células CHO , Cricetinae , Cricetulus , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Feminino , Alimentos Formulados/efeitos adversos , Quinase 3 da Glicogênio Sintase/metabolismo , Homocisteína/toxicidade , Hiper-Homocisteinemia/patologia , Hiper-Homocisteinemia/fisiopatologia , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Serina/metabolismo
13.
Ann Oncol ; 19(6): 1082-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18304964

RESUMO

Investigation of high-dose chemotherapy (HD-CT) compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and >/=10 axillary lymph nodes. From November 1993 to September 2000, 307 patients were randomized to receive after four cycles of epirubicin (90 mg/m(2)), cyclophosphamide (600 mg/m(2)) i.v. (every 21 days) and either HD-CT of cyclophosphamide (1500 mg/m(2)), thiotepa (150 mg/m(2)) and mitoxantrone (10 mg/m(2)) i.v. for four consecutive days followed by stem cell transplantation or a SD-CT of three cycles CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), 5-fluorouracil 600 mg/m(2), i.v. on day 1 and 8, respectively, every 28 days). After a median follow-up of 6.1 years, 166 events with respect to event-free survival (EFS) (SD-CT: 91, HD-CT: 75) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0.80 [95% confidence interval (0.59, 1.08)], P = 0.15. The trend to a superiority of HD-CT as compared with SD-CT with respect to EFS seems to be more pronounced in premenopausal patients as compared with postmenopausal patients and in patients with tumor grade 3 as compared with patients with tumor grade 1/2. With a follow-up of 6 years, there was a trend in favor of HD-CT with respect to EFS not being significant. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients who might benefit from HD-CT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Linfonodos/patologia , Adulto , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Estadiamento de Neoplasias , Estudos Prospectivos , Análise de Sobrevida , Tiotepa/administração & dosagem , Transplante Autólogo
14.
Ann Oncol ; 18(4): 665-71, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17185743

RESUMO

BACKGROUND: We investigated the efficacy and safety of tandem high-dose methotrexate (HD-MTX) induction followed by high-dose busulfan/thiotepa (HD-BuTT) with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiation therapy (WBRT) in patients with newly diagnosed primary central nervous system lymphoma. PATIENTS AND METHODS: Twenty-three patients were treated with HD-MTX on days 1 and 10. In case of at least a partial remission (PR), HD-BuTT followed by aPBSCT was given. Patients without response to induction or without complete remission (CR) after HD-BuTT received WBRT. RESULTS: Sixteen patients received HD-MTX and HD-BuTT achieving a CR/PR rate of 69%/13%. CR/PR rates for all patients (n = 23) were 70%/13%. There were three deaths during therapy. With longer follow-up three neurotoxic deaths occurred in irradiated patients (n = 9), while no persistent neurotoxicity was seen after HD-BuTT without subsequent WBRT. At a median follow-up of 15 months (range 1-69) median event-free survival (EFS) and overall survival (OS) for all patients were 17 and 20 months (Kaplan-Meier), after HD-BuTT 27 months and "not reached", respectively. Estimated 2-year EFS and OS were 45% and 48% for all patients versus 56% and 61% for the HD-BuTT group, respectively. CONCLUSION: MTX induction followed by HD-BuTT is an effective and very short time-on-treatment regimen. Median survival for patients treated with high-dose chemotherapy is not reached yet. The induction regimen needs optimisation. In this study WBRT was associated with a high incidence of severe neurotoxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Irradiação Craniana , Linfoma/terapia , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Idoso , Bussulfano/administração & dosagem , Neoplasias do Sistema Nervoso Central/mortalidade , Terapia Combinada , Feminino , Humanos , Linfoma/mortalidade , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Tiotepa/administração & dosagem
15.
Bone Marrow Transplant ; 37(12): 1087-91, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16699528

RESUMO

Infections during neutropaenia contribute still significantly to mortality and morbidity after high-dose therapy and autologous stem cell transplantation. Further acceleration of haemopoietic recovery seems impossible for biological reasons. Another approach to shorten neutropaenia could be to remove drugs from high-dose therapy protocols with strong contribution to immunosuppression and neutropaenia and unproven antineoplastic activity. In this retrospective matched-pair analysis, conventional busulphan/cyclophosphamide (Bu/Cy) high-dose therapy was compared to single-agent busulphan conditioning before autologous stem cell transplantation. This modification led to a significant shorter neutropaenic interval by protraction of cell decrease and to a significant mitigation of neutropaenia. After single-agent busulphan conditioning, leucocytes dropped below 1/nl at median 1.5 days later when compared to the patients from the busulphanBu/Cy control group (P=0.001). In a significant percentage of patients (n=6, 60%) leucocytes did not fall below 0.5 cells/nl at any time. In contrast, all patients from the Bu/Cy control group experienced deep neutropaenia (P=0.004). Thrombocytopaenia and requirement for transfusions of platelets or red cells were not influenced. Antineoplastic activity seemed to be preserved as determined by survival analysis. In conclusion, modification of high-dose regimen with the intention to shorten neutropaenia with preserved antitumour activity could be an approach to reduce infection-related morbidity and mortality and to consider economic necessities.


Assuntos
Transtornos Linfoproliferativos/terapia , Neutropenia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Bussulfano/economia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/economia , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/economia , Infecções/economia , Infecções/etiologia , Infecções/mortalidade , Infecções/patologia , Contagem de Leucócitos , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/economia , Transtornos Linfoproliferativos/mortalidade , Masculino , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Transfusão de Plaquetas , Estudos Retrospectivos , Transplante de Células-Tronco/economia , Transplante de Células-Tronco/mortalidade , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Trombocitopenia/economia , Trombocitopenia/mortalidade , Trombocitopenia/terapia , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/economia , Condicionamento Pré-Transplante/métodos , Transplante Autólogo
16.
Hum Mutat ; 27(5): 474-82, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16619244

RESUMO

Cystathionine beta-synthase (CBS) deficiency is a recessive genetic disorder characterized by extremely elevated levels in plasma homocysteine. Patients homozygous for the I278T or R266K mutations respond clinically to pharmacologic doses of pyridoxine, the precursor of a cofactor for the enzyme, 5'-pyridoxal phosphate (PLP). Here we test the hypothesis that these mutations are pyridoxine responsive because they lower the affinity of the enzyme for PLP. We show that recombinant R266K has 30 to 100% of the specific activity of the wild-type enzyme, while I278T only has only 1 to 5% activity. Kinetic studies show that the decreased activity in both enzymes is due to reduced turnover rate and not substrate binding. Neither I278T nor R266K appear to greatly affect multimer status of the enzyme. The R266K enzyme has reduced affinity for PLP compared to the wild-type enzyme, providing a mechanism for the pyridoxine response observed in patients. Surprisingly, the I278T enzyme does not have altered affinity for PLP. To confirm that this was not an in vitro artifact, we examined pyridoxine response in mice that stably express human I278T as their sole source of CBS activity. These mice have extremely elevated plasma homocysteine levels and do not respond significantly to large doses of pyridoxine. Our findings suggest that there may be multiple mechanisms involved in response to pyridoxine.


Assuntos
Cistationina beta-Sintase/genética , Homocistinúria/genética , Piridoxina/farmacologia , Alelos , Animais , Cistationina beta-Sintase/metabolismo , Homocisteína/sangue , Homocistinúria/tratamento farmacológico , Humanos , Cinética , Camundongos , Camundongos Transgênicos/metabolismo , Mutação , Fosfato de Piridoxal/metabolismo , Piridoxina/uso terapêutico , Proteínas Recombinantes de Fusão/metabolismo , Leveduras/genética , Leveduras/metabolismo
18.
Vox Sang ; 90(1): 53-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16359356

RESUMO

BACKGROUND AND OBJECTIVES: For timing the onset of apheresis, parameters obtained by flow cytometry and by a haematological cell analyser were compared. MATERIALS AND METHODS: Haematopoietic cell counts (n = 159) were performed by two different methods; CD34 analyses by flow cytometry, immature myeloid information (IMI) and human progenitor cell counts (HPC) by a haematological cell analyser. RESULTS: Comparing the IMI total results with CD34+ analyses (n = 159) revealed a correlation of r = 0.46 (P < 0.05). Similar results were obtained for HPC (r = 0.44; P < 0.05). CONCLUSION: The haematology analyser-based method does not allow the precise determination of absolute haematopoietic stem cell numbers and is thus not able to replace flow cytometry for the monitoring of peripheral blood stem cell counts.


Assuntos
Remoção de Componentes Sanguíneos , Citometria de Fluxo , Células-Tronco Hematopoéticas/citologia , Remoção de Componentes Sanguíneos/instrumentação , Remoção de Componentes Sanguíneos/métodos , Citometria de Fluxo/instrumentação , Citometria de Fluxo/métodos , Testes Hematológicos/instrumentação , Testes Hematológicos/métodos , Humanos , Contagem de Leucócitos/instrumentação , Contagem de Leucócitos/métodos
19.
Bone Marrow Transplant ; 37(2): 155-63, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16284608

RESUMO

We report the results of 84 patients with ALL after related (n = 46) or unrelated (n = 38) allogeneic SCT. Mean recipient age was 23 years (range: 1-60) and median follow-up was 18 months (range: 1-133). Forty-three patients were transplanted in CR1; 25 in CR2 or CR3; four were primary refractory; four in PR; eight in relapse. The conditioning regimen consisted of TBI/VP16/CY (n = 76), TBI/VP16 (n = 2), TBI/CY (n = 2), Bu/VP16/CY (n = 4). The OS at 3 years was 45% (44% unrelated, 46% related). Univariate analysis showed a significantly better OS for patients <18 years (P=0.03), mismatched sex-combination (P = 0.03), both with a stronger effect on increasing OS after unrelated SCT. Factors decreasing TRM were patient age <18 years (P = 0.004), patient CMV-seronegativity (P = 0.014), female recipient (P = 0.04). There was no significant difference in TRM and the relapse rate was similar in both donor type groups. Multivariate analysis showed that factors for increased OS which remained significant were mismatched sex-combination (RR: 0.70,95% CI: 0.51-0.93, P = 0.015), patient age < 18 years (RR: 0.66, 95% CI: 0.47-0.93, P = 0.016). A decreased TRM was found for female patients (RR: 0.56, 95% CI: 0.33-0.98, P=0.042), negative CMV status of the patient (RR: 0.57, 95% CI: 0.36-0.90, P = 0.015). Unrelated stem cell transplantation for high-risk ALL patients with no HLA-compatible family donor is justifiable.


Assuntos
Seleção do Doador , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/mortalidade , Intervalo Livre de Doença , Seleção do Doador/métodos , Feminino , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/métodos , Taxa de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
20.
Dtsch Med Wochenschr ; 130(38): 2130-4, 2005 Sep 23.
Artigo em Alemão | MEDLINE | ID: mdl-16172952

RESUMO

BACKGROUND AND OBJECTIVE: In patients with follicular lymphoma and mantle cell lymphoma circulating lymphoma cells can be detected by quantitative real-time PCR with a high sensitivity and reproducibility. With this study we wanted to ascertain whether a continuous molecular remission achieved in patients with mantle cell lymphoma and follicular lymphoma has an impact on survival of these patients. PATIENT AND METHODS: We conducted these investigations in 32 patients (24 with follicular lymphoma and 8 with mantle cell lymphoma) who were treated in a randomized trial with chemotherapy plus/minus rituximab (MCP, R-MCP). A further ten patients had follicular lymphoma (stage I and II) in long-term complete remission after radiation therapy. RESULTS: Up to 18 years after initial diagnoses of a stage I or II follicular lymphoma circulating t(14;18) positive cells could be detected in the peripheral blood. In advanced stage follicular lymphoma patients molecular remissions could only be achieved when they were treated with combined chemo-immunotherapy (MCP+R). A significantly higher relapse-free survival correlates with sustained molecular remission. In contrast, the frustrating clinical results obtained from the treatment of patients with mantle cell lymphoma corresponded to an achievement of only short molecular remissions in very few patients. CONCLUSIONS: The consequent application of quantitative real-time PCR will further improve current treatment strategies in lymphoma patients. Especially, individual treatment options can be developed for patients who do not respond to a standard chemotherapy or progression of disease is recognized, if results of molecular monitoring will be confirmed in large prospective studies.


Assuntos
Linfoma Folicular/patologia , Linfoma de Célula do Manto/patologia , Neoplasia Residual/diagnóstico , Células Neoplásicas Circulantes , Reação em Cadeia da Polimerase/métodos , Humanos , Linfoma Folicular/genética , Linfoma Folicular/terapia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapia , Neoplasia Residual/genética , Neoplasia Residual/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão
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