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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360992

RESUMO

Several protocols exist for generating megakaryocytes (MKs) and platelets from human induced pluripotent stem cells (hiPSCs) with limited efficiency. We observed previously that mesoderm induction improved endothelial and stromal differentiation. We, therefore, hypothesized that a protocol modification prior to hemogenic endothelial cell (HEC) differentiation will improve MK progenitor (MKP) production and increase platelet output. We further asked if basic media composition affects MK maturation. In an iterative process, we first compared two HEC induction protocols. We found significantly more HECs using the modified protocol including activin A and CHIR99021, resulting in significantly increased MKs. MKs released comparable platelet amounts irrespective of media conditions. In a final validation phase, we obtained five-fold more platelets per hiPSC with the modified protocol (235 ± 84) compared to standard conditions (51 ± 15; p < 0.0001). The regenerative potency of hiPSC-derived platelets was compared to adult donor-derived platelets by profiling angiogenesis-related protein expression. Nineteen of 24 angiogenesis-related proteins were expressed equally, lower or higher in hiPSC-derived compared to adult platelets. The hiPSC-platelet's coagulation hyporeactivity compared to adult platelets was confirmed by thromboelastometry. Further stepwise improvement of hiPSC-platelet production will, thus, permit better identification of platelet-mediated regenerative mechanisms and facilitate manufacture of sufficient amounts of functional platelets for clinical application.


Assuntos
Plaquetas/citologia , Diferenciação Celular , Técnicas de Reprogramação Celular/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Megacariócitos/citologia , Células Cultivadas , Meios de Cultura/química , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo
2.
Int J Mol Sci ; 21(3)2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991850

RESUMO

Microglia are first-line defense antigen-presenting phagocytes in the central nervous system. Activated microglial cells release pro-inflammatory cytokines and can trigger an oxidative burst. The amino acid glycine exerts anti-inflammatory, immunomodulatory and cytoprotective effects and influences cell volume regulation. This study aimed to investigate the role of glycine in the modulation of inflammatory processes in mouse BV-2 microglial cells. Inflammatory stress was induced by lipopolysaccharide/interferon-γ (LPS/IFN-γ) treatment for 24 h in the absence or presence of 1 or 5 mM glycine. Cells were analyzed by flow cytometry for cell volume, side scatter, apoptosis/necrosis and expression of activation-specific surface markers. Apoptosis progression was monitored by life cell imaging. Reduced glutathione/oxidized glutathione (GSH/GSSG) ratios and release of the pro-inflammatory cytokines IL-6 and TNF-α were measured using luminescence-based assays and ELISA, respectively. We found that LPS/IFN-γ-induced apoptosis was decreased and the fraction of living cells was increased by glycine. Expression of the surface markers CD11b, CD54 and CD80 was dose-dependently increased, while IL-6 and TNF-α release was not altered compared to LPS/IFN-γ-treated cells. We showed that in BV-2 microglial cells glycine improves viability and counteracts deleterious responses to LPS/IFN-γ, which might be relevant in neurodegenerative processes associated with inflammation, like Alzheimer's or Parkinson's disease.


Assuntos
Apoptose/efeitos dos fármacos , Glicina/farmacocinética , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Antígenos CD/metabolismo , Linhagem Celular Transformada , Glutationa/metabolismo , Humanos , Interleucina-6/metabolismo , Camundongos , Microglia/patologia , Oxirredução/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fator de Necrose Tumoral alfa/metabolismo
3.
Sci Immunol ; 4(37)2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278120

RESUMO

Tissue-resident memory T cells (TRM) persist locally in nonlymphoid tissues where they provide frontline defense against recurring insults. TRM at barrier surfaces express the markers CD103 and/or CD69, which function to retain them in epithelial tissues. In humans, neither the long-term migratory behavior of TRM nor their ability to reenter the circulation and potentially migrate to distant tissue sites has been investigated. Using tissue explant cultures, we found that CD4+CD69+CD103+ TRM in human skin can down-regulate CD69 and exit the tissue. In addition, we identified a skin-tropic CD4+CD69-CD103+ population in human lymph and blood that is transcriptionally, functionally, and clonally related to the CD4+CD69+CD103+ TRM population in the skin. Using a skin xenograft model, we confirmed that a fraction of the human cutaneous CD4+CD103+ TRM population can reenter circulation and migrate to secondary human skin sites where they reassume a TRM phenotype. Thus, our data challenge current concepts regarding the strict tissue compartmentalization of CD4+ T cell memory in humans.


Assuntos
Antígenos CD/imunologia , Sangue/imunologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica/imunologia , Cadeias alfa de Integrinas/imunologia , Antígenos CD/sangue , Células Cultivadas , Voluntários Saudáveis , Humanos , Cadeias alfa de Integrinas/sangue , Pele/citologia , Pele/imunologia
4.
Glia ; 67(8): 1510-1525, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31038798

RESUMO

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.


Assuntos
Envelhecimento/fisiologia , Células-Tronco Mesenquimais/fisiologia , Oligodendroglia/fisiologia , Remielinização/fisiologia , Animais , Células Cultivadas , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Feminino , Masculino , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos
5.
Cardiovasc Diabetol ; 17(1): 71, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29773079

RESUMO

BACKGROUND: Early glucose lowering intervention in subjects with type 2 diabetes mellitus was demonstrated to be beneficial in terms of micro- and macrovascular risk reduction. However, most of currently ongoing cardiovascular outcome trials are performed in subjects with manifest atherosclerosis and long-standing diabetes. Therefore, the aim of this study is to investigate the effects of the dipeptidylpeptidase-4 inhibitor linagliptin in subjects with coronary artery disease (CAD) but early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements. METHODS: In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2 h glucose > 200 mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy and an HbA1c < 75 mmol/mol) and established CAD. Participants were randomized to receive either linagliptin (5 mg) once daily orally or placebo for 12 weeks. The primary outcome was the change in flow mediated dilatation (FMD). The secondary objective was to investigate the effect of linagliptin treatment on arginine bioavailability ratios [Global arginine bioavailability ratio (GABR) and arginine to ornithine ratio (AOR)]. Arginine, ornithine and citrulline were measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. GABR was calculated by L-arginine divided by the sum of (L-ornithine plus L-citrulline). The AOR was calculated by dividing L-arginine by L-ornithine levels. Group comparisons were calculated by using a two-sample t-test with Satterthwaite adjustment for unequal variances. RESULTS: We investigated 43 patients (21% female) with a mean age of 63.3 ± 8.2 years. FMD at baseline was 3.5 ± 3.1% in the linagliptin group vs. 4.0 ± 2.9% in the placebo group. The change in mean FMD in the linagliptin group was not significantly different compared to the change in the placebo group (0.43 ± 4.84% vs. - 0.45 ± 3.01%; p = 0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR; p = 0.608 and AOR; p = 0.549). CONCLUSION: Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or the arginine bioavailability ratios. Trial registration ClinicalTrials.gov, NCT02350478 ( https://clinicaltrials.gov/ct2/show/NCT02350478 ).


Assuntos
Glicemia/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Linagliptina/uso terapêutico , Lipídeos/sangue , Vasodilatação/efeitos dos fármacos , Idoso , Arginina/sangue , Áustria , Biomarcadores/sangue , Glicemia/metabolismo , Citrulina/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Linagliptina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ornitina/sangue , Período Pós-Prandial , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
6.
Theranostics ; 8(5): 1421-1434, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29507631

RESUMO

Intravascular transplantation of tissue factor (TF)-bearing cells elicits an instant blood-mediated inflammatory reaction (IBMIR) resulting in thrombotic complications and reduced engraftment. Here we studied the hemocompatibility of commonly used human white adipose tissue (WAT), umbilical cord (UC) and bone marrow stromal cells (BMSC) and devised a possible strategy for safe and efficient stromal cell transplantation. Methods: Stromal cell identity, purity, and TF expression was tested by RTQ-PCR, flow cytometry and immunohistochemistry. Pro-coagulant activity and fibrin clot formation/stabilization was measured In Vitro by viscoelastic rotational plasma-thromboelastometry and in vivo by injecting sorted human stromal cells intravenously into rats. The impact of TF was verified in factor VII-deficient plasma and by sort-depleting TF/CD142+ BMSC. Results: We found significantly less TF expression by a subpopulation of BMSC corresponding to reduced pro-coagulant activity. UC and WAT stroma showed broad TF expression and durable clotting. Higher cell numbers significantly increased clot formation partially dependent on coagulation factor VII. Depleting the TF/CD142+ subpopulation significantly ameliorated BMSC's hemocompatibility without affecting immunomodulation. TF-deficient BMSC did not produce thromboembolism in vivo, comparing favorably to massive intravascular thrombosis induction by TF-expressing stromal cells. Conclusion: We demonstrate that plasma-based thromboelastometry provides a reliable tool to detect pro-coagulant activity of therapeutic cells. Selecting TF-deficient BMSC is a novel strategy for improving cell therapy applicability by reducing cell dose-dependent IBMIR risk. The particularly strong pro-coagulant activity of UC and WAT preparations sounds an additional note of caution regarding uncritical systemic application of stromal cells, particularly from non-hematopoietic extravascular sources.


Assuntos
Teste de Materiais , Células-Tronco Mesenquimais/metabolismo , Tromboplastina/deficiência , Adulto , Animais , Coagulação Sanguínea , Contagem de Células , Tamanho Celular , Transplante de Células , Células Cultivadas , Feminino , Humanos , Imunomodulação , Masculino , Pessoa de Meia-Idade , Ratos , Fatores de Risco , Tromboembolia/etiologia , Tromboembolia/patologia , Tromboplastina/metabolismo , Adulto Jovem
7.
Nucleic Acids Res ; 45(17): 10259-10269, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28973459

RESUMO

Functional impairment or complete loss of type VII collagen, caused by mutations within COL7A1, lead to the severe recessive form of the skin blistering disease dystrophic epidermolysis bullosa (RDEB). Here, we successfully demonstrate RNA trans-splicing as an auspicious repair option for mutations located in a wide range of exons by fully converting an RDEB phenotype in an ex vivo pre-clinical mouse model based on xenotransplantation. Via a self-inactivating (SIN) lentiviral vector a 3' RNA trans-splicing molecule, capable of replacing COL7A1 exons 65-118, was delivered into type VII collagen deficient patient keratinocytes, carrying a homozygous mutation in exon 80 (c.6527insC). Following vector integration, protein analysis of an isolated corrected single cell clone showed secretion of the corrected type VII collagen at similar levels compared to normal keratinocytes. To confirm full phenotypic and long-term correction in vivo, patches of skin equivalents expanded from the corrected cell clone were grafted onto immunodeficient mice. Immunolabelling of 12 weeks old skin specimens showed strong expression of human type VII collagen restricted to the basement membrane zone. We demonstrate that the RNA trans-splicing technology combined with a SIN lentiviral vector is suitable for an ex vivo molecular therapy approach and thus adaptable for clinical application.


Assuntos
Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/terapia , Terapia Genética/métodos , Vetores Genéticos/uso terapêutico , RNA/uso terapêutico , Trans-Splicing , Animais , Membrana Basal/metabolismo , Células Cultivadas , Colágeno Tipo VII/deficiência , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Vetores Genéticos/genética , Vetores Genéticos/farmacologia , Xenoenxertos , Humanos , Queratinócitos/metabolismo , Queratinócitos/transplante , Lentivirus/genética , Camundongos , Modelos Animais , RNA/administração & dosagem , RNA/genética , Precursores de RNA/genética , Precursores de RNA/metabolismo , Transplante de Pele , Transgenes
8.
Stem Cell Res Ther ; 6: 236, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26620155

RESUMO

The inherent immunomodulatory capacity of mesenchymal stem/progenitor cells (MSPCs) encouraged initiation of multiple clinical trials. Release criteria for therapeutic MSPCs cover identity, purity and safety but appropriate potency assessment is often missing. Reports on functional heterogeneity of MSPCs created additional uncertainty regarding donor and organ/source selection. We established a robust immunomodulation potency assay based on pooling responder leukocytes to minimize individual immune response variability. Comparing various MSPCs revealed significant potency inconsistency and generally diminished allo-immunosuppression compared to dose-dependent inhibition of mitogenesis. Gamma-irradiation to block unintended MSPC proliferation did not prohibit chondrogenesis and osteogenesis in vivo, indicating the need for alternative safety strategies.


Assuntos
Bioensaio/métodos , Imunomodulação , Células-Tronco Mesenquimais/imunologia , Doadores de Tecidos , Adulto , Animais , Proliferação de Células , Células Cultivadas , Raios gama , Humanos , Células-Tronco Mesenquimais/efeitos da radiação , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Tolerância a Radiação , Linfócitos T/citologia , Linfócitos T/imunologia , Adulto Jovem
9.
Oncotarget ; 6(14): 12048-60, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25895128

RESUMO

Homing to distinct lymphoid organs enables chronic lymphocytic leukemia (CLL) cells to receive pro-survival and proliferative signals. Cytogenetic aberrations can significantly affect CLL cell compartmentalization. Trisomy 12 (tri12) defines a CLL subgroup with specific clinical features and increased levels of the negative prognostic marker CD49d, the α4-subunit of the integrin VLA-4, which is a key regulator of CLL cell homing to bone marrow (BM). Chemokine-induced inside-out VLA-4 activation, particularly via the CXCL12-CXCR4 axis, increases the arrest of various cell types on VCAM-1 presenting endothelium. Here, we demonstrate that high CD49d expression in tri12 CLL is accompanied by decreased CXCR4 expression. Dissecting functional consequences of these alterations, we observed that tri12 CLL cell homing to murine BM is not affected by CXCR4-CXCL12 blockage using AMD3100 or olaptesed pegol/NOX-A12. In line, CCL21-CCR7 rather than CXCL12-CXCR4 interactions triggered VLA-4-mediated arrests of tri12 CLL cells to VCAM-1 under blood flow conditions. Concordantly, in real-time kinetic analyses we found CCL21 but not CXCL12 being capable to induce inside-out VLA-4 conformational changes in this CLL subgroup. Our results provide novel insights into the peculiar clinico-biological behaviour of tri12 CLL and emphasize its specific chemokine and integrin utilization during pathophysiologically and therapeutically relevant interactions with the microenvironment.


Assuntos
Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Animais , Humanos , Camundongos , Transdução de Sinais
10.
Ann Hematol ; 93(3): 361-74, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24288111

RESUMO

The interactions of chronic lymphocytic leukemia cells with the microenvironment in secondary lymphoid tissues and the bone marrow are known to promote CLL cell survival and proliferation. CD38 and CD49d are both independent prognostic risk parameters in CLL with important roles in shaping these interactions. Both are reported to influence CLL cell trafficking between blood and lymphoid organs as well as their survival and proliferation within the lymphoid organs, thereby impacting the pathophysiology of the disease. The expression of CD38 and CD49d is associated in the majority of cases, and they exist as part of macromolecular complexes. Here, we review the current evidence for the individual and associated contributions of these molecules to CLL pathophysiology.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Biomarcadores Tumorais/metabolismo , Integrina alfa4/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Glicoproteínas de Membrana/metabolismo , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , ADP-Ribosil Ciclase 1/sangue , Animais , Biomarcadores Tumorais/sangue , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Humanos , Integrina alfa4/sangue , Integrina alfa4beta1/sangue , Integrina alfa4beta1/metabolismo , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Glicoproteínas de Membrana/sangue , Proteínas de Neoplasias/sangue , Prognóstico , Microambiente Tumoral
11.
PLoS One ; 6(8): e23758, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21876768

RESUMO

BACKGROUND: VLA-4 and CD38 predict a poor clinical outcome in chronic lymphocytic leukemia (CLL). We used CLL samples with discordant VLA-4/CD38 risk to address their individual roles in human bone marrow infiltration (BM), CLL cell homing to murine BM, and in supportive CLL cell-stromal cell interactions. METHODS: VLA-4, CD38, and Ki-67 expression was measured in CLL cells from peripheral blood (PB) and bone marrow (BM) aspirates. CLL BM infiltration rates, routinely determined by Pathology, were correlated to VLA-4 and CD38 expression. Short-term homing capacity of CLL cells was evaluated by adoptive transfer experiments. CLL cell viability and adhesion in stromal cell co-culture was determined. RESULTS: About 20% of CLL samples in our cohort displayed discordant VLA-4 and CD38 risk, with either high VLA-4 and low CD38 risk or vice versa. Using particularly such samples, we observed that VLA-4, and not CD38, was responsible for recirculation of CLL cells to murine BM. Human BM infiltration was also significantly higher in patients with high VLA-4 risk but not high CD38 risk. However, both molecules acted as independent prognostic markers. While both VLA-4 and CD38 expression were increased in BM-derived CLL cells, and VLA-4+ and CD38+ subpopulations showed enriched Ki-67 expression, VLA-4 did not contribute to CLL cell protection by stromal cells in vitro. CONCLUSIONS: Our data argue for a prominent role of VLA-4 but not CD38 expression in the homing of CLL cells to BM niches and in human BM infiltration, but only a limited role in their protection by stromal cells.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Medula Óssea/patologia , Integrina alfa4beta1/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Infiltração Leucêmica/patologia , ADP-Ribosil Ciclase 1/sangue , Animais , Apoptose , Linfócitos B/imunologia , Medula Óssea/metabolismo , Adesão Celular , Contagem de Células , Feminino , Humanos , Imuno-Histoquímica , Integrina alfa4beta1/sangue , Antígeno Ki-67/metabolismo , Leucemia Linfocítica Crônica de Células B/sangue , Tecido Linfoide/patologia , Masculino , Camundongos , Fatores de Risco , Células Estromais/patologia , Análise de Sobrevida
12.
Cancer Res ; 70(18): 7336-44, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20823161

RESUMO

Emerging evidence suggests that the survival of B-cell chronic lymphocytic leukemia (CLL) cells is dependent on microenvironmental influences such as antigenic stimulation and support by stromal cells. Akt, also known as protein kinase B, is a central component in prosurvival signaling downstream of these events. We investigated the role of Akt and its modulation by the protooncogene T-cell leukemia 1a (Tcl1a) in the survival pathways of primary CLL samples and CLL-derived prolymphocytic cell lines MEC-1 and MEC-2. Akt activation was increased by the protective presence of human bone marrow stromal cells and B-cell receptor mimicking signals but antagonized by direct Akt blockade with the novel specific inhibitor AiX, with preferential apoptosis induction in CLL cells with an unmutated immunoglobulin status, which predicts poor clinical outcome. In addition, we found a direct interaction of Akt with Tcl1a in an endogenous coimmunoprecipitation assay. Confirming the critical role of Tcl1a in modulating Akt signaling, Akt activation was enhanced by overexpressing Tcl1a in CLL. In contrast, decreasing Tcl1a levels by small interfering RNA reduced Akt activation in the fludarabine-insensitive CLL cell line MEC-2 and sensitized the malignant cells to fludarabine treatment. In summary, our data reveal a significant role for the Akt-Tcl1a axis in CLL survival and propose a further evaluation of this interplay for targeting chemoresistance phenomena.


Assuntos
Leucemia Linfocítica Crônica de Células B/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Oxazinas/farmacologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , RNA Interferente Pequeno/genética , Transdução de Sinais , Transfecção
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