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1.
BMC Palliat Care ; 23(1): 58, 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38418974

RESUMEN

BACKGROUND: Recent exercise intervention studies have shown promising results in improving quality of life (QoL) and physical function (PF) in diverse chronic disease and advanced cancer patients. However, the effects of structured exercise in palliative care patients, having different therapeutic needs, lower life expectancies and PFs remain unknown. This study primarily aimed to assess the feasibility of an exercise intervention with follow-up by analysing recruitment numbers, screening procedures, acceptability, preferences, and safety of the exercise intervention as well as retention in follow-up. Our secondary aims related to changes in QoL and PF. METHODS: This study comprised of a one-arm design without a control group. Over 6 months, every in-hospital palliative care unit (PCU) patient was screened for eligibility. Eligible patients were asked to participate in a 2-week exercise intervention consisting of resistance training and/or endurance training with moderate or high intensity based on personal preferences and a 4-week follow-up. Before and after the exercise intervention, QoL and PF were assessed and a qualitative interview after the intervention addressed expectations and experiences of the exercise intervention. For follow-up, patients were provided with information on independent training and after 1 and 4 weeks a QoL assessment and qualitative interview were conducted. RESULTS: Of 124 patients screened, 10 completed the intervention with an adherence rate of (80 ± 25%), of which 6 patients completed follow-up. Endurance training was the most performed training type and only a few minor adverse events occurred in certain or likely connection to the exercise intervention. While physical QoL and PF measured by arm curl strength and time up and go performance improved, mental QoL and the other PF tests remained unchanged. CONCLUSION: Despite the challenges that were faced in our screening and testing process, that are specific to the palliative patient population with their unique therapeutic requirements and varying mental-/ physical capabilities, we discovered the 2-week exercise intervention to be feasible, safe, and well tolerated by palliative care patients. Moreover, it seems that short-term improvements in QoL and PF are possible. Further full scale studies are required to confirm our findings. TRIAL REGISTRATION: The study was retrospectively registered on 25.01.2022 in the German Clinical Trials Register (DRKS00027861).


Asunto(s)
Cuidados Paliativos , Calidad de Vida , Humanos , Estudios de Factibilidad , Ejercicio Físico , Terapia por Ejercicio
2.
J Cell Mol Med ; 27(21): 3363-3377, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37753803

RESUMEN

Activating point mutations of the RAS gene act as driver mutations for a subset of precursor-B cell acute lymphoblastic leukaemias (pre-B ALL) and represent an ambitious target for therapeutic approaches. The X box-binding protein 1 (XBP1), a key regulator of the unfolded protein response (UPR), is critical for pre-B ALL cell survival, and high expression of XBP1 confers poor prognosis in ALL patients. However, the mechanism of XBP1 activation has not yet been elucidated in RAS mutated pre-B ALL. Here, we demonstrate that XBP1 acts as a downstream linchpin of the IL-7 receptor signalling pathway and that pharmacological inhibition or genetic ablation of XBP1 selectively abrogates IL-7 receptor signalling via inhibition of its downstream effectors, JAK1 and STAT5. We show that XBP1 supports malignant cell growth of pre-B NRASG12D ALL cells and that genetic loss of XBP1 consequently leads to cell cycle arrest and apoptosis. Our findings reveal that active XBP1 prevents the cytotoxic effects of a dual PI3K/mTOR pathway inhibitor (BEZ235) in pre-B NRASG12D ALL cells. This implies targeting XBP1 in combination with BEZ235 as a promising new targeted strategy against the oncogenic RAS in NRASG12D -mutated pre-B ALL.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Genes ras , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transducción de Señal , Respuesta de Proteína Desplegada/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas de la Membrana/genética , GTP Fosfohidrolasas/genética , Proteína 1 de Unión a la X-Box/genética
3.
PLoS One ; 17(10): e0268352, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36194587

RESUMEN

Acute lymphoblastic leukemia (ALL) is a disease of lymphoid progenitor cells with an often aggressive course and is commonly caused by the BCR-ABL fusion gene t(9;22) in adults. This fusion gene encodes a constitutively active tyrosine kinase that can be effectively inhibited by tyrosine kinase inhibitors (TKIs), with imatinib being the paradigmatic agent of this class. However, BCR-ABL+ ALL cells rapidly develop mutations against many of the available TKIs, and consecutive disease relapse still results in an overall unfavorable prognosis for patients with this disease. To date, allogeneic stem cell transplantation is the only known curative therapeutic option for the mostly elderly patients with BCR-ABL+ ALL. The discrepancy between the limited therapeutic armamentarium and the growing therapeutic need in an aging population is therefore a reason to test drug combinations against BCR-ABL+ ALL. In this study, we demonstrate that the combination of TKIs with proteasome inhibitors efficiently and under certain conditions synergistically exerts cytotoxic effects in BCR-ABL+ ALL cells in vitro with respect to the induction of apoptosis. Both sole and combined treatment of BCR-ABL+ ALL with the proteasome inhibitors bortezomib and ixazomib, respectively, and TKI causes a significantly greater reduction in cell viability than TKI treatment alone in both BCR-ABL+ cell lines TOM-1 and BV-173. In BV-173 cells, we observed a significant reduction in cell viability to only 1.26%±0.46% with bortezomib treatment and 1.57±0.7% with combination treatment, whereas cells treated with dasatinib alone still had a viable percentage of 40.58±2.6%. Similar results were obtained when ixazomib was applied to both cell lines, and apoptosis was induced in both cases (93.36%±2.7% apoptotic BV-173 cells when treated with ixazomib and TKI). The combination of TKI and proteasome inhibitor is efficient in vitro, potentially expanding the spectrum of therapeutic options for patients with BCR-ABL+ ALL.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Anciano , Compuestos de Boro , Bortezomib/farmacología , Bortezomib/uso terapéutico , Dasatinib/farmacología , Dasatinib/uso terapéutico , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/metabolismo , Glicina/análogos & derivados , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Complejo de la Endopetidasa Proteasomal , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico
5.
Schmerz ; 36(5): 371-380, 2022 Oct.
Artículo en Alemán | MEDLINE | ID: mdl-36098811

RESUMEN

Specialized outpatient palliative care (SAPV) was introduced by the legislature in 2007 in § 37b of the German Social Code Book V (SGBV) as a form of care for people with a life-limiting illness and an increased complexity of care. It is therefore only required by some of the palliative patients. It is intended to avoid unnecessary hospital admissions and to enable those affected to remain in their home environment in a dignified manner despite a complex illness and to be accompanied there until death. Initially introduced as a form of care for adults, the need for expansion to children and adolescents with life-limiting illnesses soon became apparent, so that care was supplemented in 2011 with specialized pediatric palliative care (SAPPV). Both SAPV and SAPPV involve the use of a specialized and multiprofessional palliative care team (PCT), which is characterized by 24­h accessibility and special qualifications, thus providing comprehensive support. This is provided in addition to general outpatient palliative care (AAPV) and aims to maintain, promote and, if possible, improve the quality of life and self-determination at the end of life as much as possible. The SAPV is a health insurance benefit and requires a prescription via form 63 by a physician.


Asunto(s)
Servicios de Atención de Salud a Domicilio , Cuidado Terminal , Adolescente , Adulto , Niño , Alemania , Humanos , Pacientes Ambulatorios , Cuidados Paliativos , Prescripciones , Calidad de Vida
6.
BMC Cancer ; 22(1): 735, 2022 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-35790913

RESUMEN

BACKGROUND: The therapeutic armamentarium in multiple myeloma has been significantly broadened by proteasome inhibitors, highly efficient means in controlling of multiple myeloma. Despite the developments of therapeutic regimen in treatment of multiple myeloma, still the complete remission requires a novel therapeutic strategy with significant difference in outcomes. Proteasome inhibitors induce autophagy and ER stress, both pivotal pathways for protein homeostasis. Recent studies showed that the IRE1α-XBP1 axis of the unfolded protein response (UPR) is up-regulated in multiple myeloma patients. In addition, XBP1 is crucial for the maintenance of viability of acute lymphoblastic leukemia (ALL). RESULTS: We analyzed the efficacy of targeting IRE1α-XBP1 axis and autophagy in combination with proteasome inhibitor, ixazomib in treatment of multiple myeloma. In this present study, we first show that targeting the IRE1α-XBP1 axis with small molecule inhibitors (STF-083010, A106) together with the ixazomib induces cell cycle arrest with an additive cytotoxic effect in multiple myeloma. Further, we examined the efficacy of autophagy inhibitors (bafilomycin A, BAF and chloroquine, CQ) together with ixazomib in multiple myeloma and observed that this combination treatment synergistically reduced cell viability in multiple myeloma cell lines (viable cells Ixa: 51.8 ± 3.3, Ixa + BAF: 18.3 ± 7.2, Ixa + CQ: 38.4 ± 3.7) and patient-derived multiple myeloma cells (Ixa: 59.6 ± 4.4, Ixa + CQ: 7.0 ± 2.1). We observed, however, that this combined strategy leads to activation of stress-induced c-Jun N-terminal kinase (JNK). Cytotoxicity mediated by combined proteasome and autophagy inhibition was reversed by addition of the specific JNK inhibitor JNK-In-8 (viable cells: Ixa + BAF: 11.6 ± 7.0, Ixa + BAF + JNK-In-8: 30.9 ± 6.1). CONCLUSION: In this study we showed that combined inhibition of autophagy and the proteasome synergistically induces cell death in multiple myeloma. Hence, we consider the implication of pharmaceutical inhibition of autophagy together with proteasome inhibition and UPR-directed therapy as promising novel in vitro treatment strategy against multiple myeloma.


Asunto(s)
Mieloma Múltiple , Inhibidores de Proteasoma , Apoptosis , Autofagia , Benzamidas , Línea Celular Tumoral , Endorribonucleasas , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Proteínas Serina-Treonina Quinasas , Piridinas , Pirimidinas
7.
Carcinogenesis ; 42(2): 272-284, 2021 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-32915195

RESUMEN

BCR-ABL1-positive acute lymphoblastic leukemia (ALL) cell survival is dependent on the inositol-requiring enzyme 1 alpha (IRE1α) branch of the unfolded protein response. In the current study, we have focused on exploring the efficacy of a simultaneous pharmacological inhibition of BCR-ABL1 and IRE1α in Philadelphia-positive (Ph+) ALL using tyrosine kinase inhibitor (TKI) nilotinib and the IRE1α inhibitor MKC-8866. The combination of 0.5 µM nilotinib and 30 µM MKC-8866 in Ph+ ALL cell lines led to a synergistic effect on cell viability. To mimic this dual inhibition on a genetic level, pre-B-cells from conditional Xbp1+/fl mice were transduced with a BCR-ABL1 construct and with either tamoxifen-inducible cre or empty vector. Cells showed a significant sensitization to the effect of TKIs after the induction of the heterozygous deletion. Finally, we performed a phosphoproteomic analysis on Ph+ ALL cell lines treated with the combination of nilotinib and MKC-8866 to identify potential targets involved in their synergistic effect. An enhanced activation of p38 mitogen-activated protein kinase α (p38α MAPK) was identified. In line with this findings, p38 MAPK and, another important endoplasmic reticulum-stress-related kinase, c-Jun N-terminal kinase (JNK) were found to mediate the potentiated cytotoxic effect induced by the combination of MKC-8866 and nilotinib since the targeting of p38 MAPK with its specific inhibitor BIRB-796 or JNK with JNK-in-8 hindered the synergistic effect observed upon treatment with nilotinib and MKC-8866. In conclusion, the identified combined action of nilotinib and MKC-8866 might represent a successful therapeutic strategy in high-risk Ph+ ALL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Endorribonucleasas/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Mutaciones Letales Sintéticas/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/farmacología , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Proteínas de Fusión bcr-abl/genética , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Ratones Transgénicos , Morfolinas/farmacología , Morfolinas/uso terapéutico , Naftalenos/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Cultivo Primario de Células , Pirazoles/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Proteína 1 de Unión a la X-Box/genética , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
8.
BMC Cancer ; 19(1): 658, 2019 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-31272418

RESUMEN

BACKGROUND: Expression of Bcr-Abl in hematopoietic stem cells is sufficient to cause chronic myeloid leukemia (CML) and tyrosine kinase inhibitors (TKI) induce molecular remission in the majority of CML patients. However, the disease driving stem cell population is not fully targeted by TKI therapy, and leukemic stem cells (LSC) capable of re-inducing the disease can persist. Single-cell RNA-sequencing technology recently identified an enriched inflammatory gene signature with TNFα and TGFß being activated in TKI persisting quiescent LSC. Here, we studied the effects of human TNFα antibody infliximab (IFX), which has been shown to induce anti-inflammatory effects in mice, combined with TKI treatment on LSC function. METHODS: We first performed GSEA-pathway analysis using our microarray data of murine LSK cells (lin-; Sca-1+; c-kit+) from the SCLtTA/Bcr-Abl CML transgenic mouse model. Bcr-Abl positive cell lines were generated by retroviral transduction. Clonogenic potential was assessed by CFU (colony forming unit). CML mice were treated with nilotinib or nilotinib plus infliximab, and serial transplantation experiments were performed. RESULTS: Likewise to human CML, TNFα signaling was specifically active in murine CML stem cells, and ectopic expression of Bcr-Abl in murine and human progenitor cell lines induced TNFα expression. In vitro exposure to human (IFX) or murine (MP6-XT22) TNFα antibody reduced clonogenic growth of CML cells. Interestingly, TNFα antibody treatment enhanced TKI-induced effects on immature cells in vitro. Additionally, in transplant and serial transplant experiments, using our transgenic CML mouse model, we could subsequently show that IFX therapy boosted TKI-induced effects and further reduced the proportion of malignant stem cells in vivo. CONCLUSION: TNFα signaling is induced in CML stem cells, and anti-inflammatory therapy enhances TKI-induced decline of LSC, confirming that successful targeting of persisting CML stem cells can be enhanced by addressing their malignant microenvironment simultaneously.


Asunto(s)
Antiinflamatorios/uso terapéutico , Infliximab/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Infliximab/farmacología , Ratones , Ratones Transgénicos , Células Madre Neoplásicas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transducción Genética , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Theranostics ; 8(5): 1389-1398, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29507628

RESUMEN

Cancer proteomics is the manifestation of relevant biological processes in cancer development. Thus, it reflects the activities of tumor cells, host-tumor interactions, and systemic responses to cancer therapy. To understand the causal effects of tumorigenesis or therapeutic intervention, longitudinal studies are greatly needed. However, most of the conventional mouse experiments are unlikely to accommodate frequent collection of serum samples with a large enough volume for multiple protein assays towards single-object analysis. Here, we present a technique based on magneto-nanosensors to longitudinally monitor the protein profiles in individual mice of lymphoma models using a small volume of a sample for multiplex assays. Methods: Drug-sensitive and -resistant cancer cell lines were used to develop the mouse models that render different outcomes upon the drug treatment. Two groups of mice were inoculated with each cell line, and treated with either cyclophosphamide or vehicle solution. Serum samples taken longitudinally from each mouse in the groups were measured with 6-plex magneto-nanosensor cytokine assays. To find the origin of IL-6, experiments were performed using IL-6 knock-out mice. Results: The differences in serum IL-6 and GCSF levels between the drug-treated and untreated groups were revealed by the magneto-nanosensor measurement on individual mice. Using the multiplex assays and mouse models, we found that IL-6 is secreted by the host in the presence of tumor cells upon the drug treatment. Conclusion: The multiplex magneto-nanosensor assays enable longitudinal proteomic studies on mouse tumor models to understand tumor development and therapy mechanisms more precisely within a single biological object.


Asunto(s)
Linfoma/metabolismo , Magnetismo/instrumentación , Nanotecnología/instrumentación , Proteómica , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Linfoma/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Supervivencia , Regulación hacia Arriba
10.
Ann Hematol ; 95(5): 707-18, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26916570

RESUMEN

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations.


Asunto(s)
Hemorragia/etiología , Técnicas Hemostáticas , Trastornos Mieloproliferativos/complicaciones , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Factores de Coagulación Sanguínea/uso terapéutico , Pérdida de Sangre Quirúrgica/prevención & control , Transfusión Sanguínea , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/patología , Ensayos Clínicos como Asunto , Contraindicaciones , Desamino Arginina Vasopresina/uso terapéutico , Manejo de la Enfermedad , Procedimientos Quirúrgicos Electivos , Hemorragia/diagnóstico , Hemorragia/prevención & control , Hemorragia/terapia , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/complicaciones , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/tratamiento farmacológico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Hígado/fisiopatología , Estudios Multicéntricos como Asunto , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pruebas de Función Plaquetaria , Transfusión de Plaquetas , Hemorragia Posoperatoria/etiología , Hemorragia Posoperatoria/prevención & control , Hemorragia Posoperatoria/terapia , Trombofilia/tratamiento farmacológico , Trombofilia/etiología , Ácido Tranexámico/uso terapéutico , Enfermedades de von Willebrand/etiología , Factor de von Willebrand/análisis
11.
Blood ; 125(9): 1444-51, 2015 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-25499760

RESUMEN

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is initiated and driven by the oncogenic fusion protein BCR-ABL, a constitutively active tyrosine kinase. Despite major advances in the treatment of this highly aggressive disease with potent inhibitors of the BCR-ABL kinase such as dasatinib, patients in remission frequently relapse due to persistent minimal residual disease possibly supported, at least in part, by salutary cytokine-driven signaling within the hematopoietic microenvironment. Using a mouse model of Ph+ ALL that accurately mimics the genetics, clinical behavior, and therapeutic response of the human disease, we show that a combination of 2 agents approved by the US Food and Drug Administration (dasatinib and ruxolitinib, which inhibit BCR-ABL and Janus kinases, respectively), significantly extends survival by targeting parallel signaling pathways. Although the BCR-ABL kinase cancels the cytokine requirement of immature leukemic B cells, dasatinib therapy restores cytokine dependency and sensitizes leukemic cells to ruxolitinib. As predicted, ruxolitinib alone had no significant antileukemic effect in this model, but it prevented relapse when administered with dasatinib. The combination of dasatinib, ruxolitinib, and the corticosteroid dexamethasone yielded more durable remissions, in some cases after completion of therapy, avoiding the potential toxicity of other cytotoxic chemotherapeutic agents.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Recurrencia Local de Neoplasia/tratamiento farmacológico , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Factor 1 de Ribosilacion-ADP/fisiología , Animales , Western Blotting , Dasatinib , Dexametasona/administración & dosificación , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Interleucina-7/genética , Interleucina-7/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Nitrilos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Inducción de Remisión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Tasa de Supervivencia , Tiazoles/administración & dosificación , Células Tumorales Cultivadas
12.
Nature ; 510(7505): 402-6, 2014 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-24805236

RESUMEN

PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing. PTEN dephosphorylates phosphatidylinositol (3,4,5)-triphosphate, thereby opposing the activity of class I phosphatidylinositol 3-kinases that mediate growth- and survival-factor signalling through phosphatidylinositol 3-kinase effectors such as AKT and mTOR. To determine whether continued PTEN inactivation is required to maintain malignancy, here we generate an RNA interference-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal Pten knockdown in the haematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukaemia. Notably, reactivation of PTEN mainly reduced T-cell leukaemia dissemination but had little effect on tumour load in haematopoietic organs. Leukaemia infiltration into the intestine was dependent on CCR9 G-protein-coupled receptor signalling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.


Asunto(s)
Leucemia/enzimología , Leucemia/fisiopatología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Microambiente Tumoral/fisiología , Animales , Quimiocinas/metabolismo , Técnicas de Silenciamiento del Gen , Leucemia/genética , Ratones Transgénicos , Fosfatidilinositol 3-Quinasas/metabolismo , Interferencia de ARN , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal
13.
Nature ; 487(7406): 244-8, 2012 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-22722845

RESUMEN

Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked 'clusters', suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, we establish the polyamine-hypusine axis as a new tumour suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas and co-suppression of both genes promotes lymphomagenesis in mice. Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway.


Asunto(s)
Linfoma de Células B/genética , Lisina/análogos & derivados , Poliaminas/química , Proteínas Supresoras de Tumor/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Redes Reguladoras de Genes , Pruebas Genéticas , Humanos , Linfoma de Células B/fisiopatología , Lisina/química , Ratones , Ratones Endogámicos C57BL , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Reproducibilidad de los Resultados
14.
Blood ; 119(22): 5215-20, 2012 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-22510874

RESUMEN

Osteopontin (OPN) is a glycoprotein that is secreted by osteoblasts and hematopoietic cells. OPN suppresses the proliferation of hematopoietic stem cells in vitro and may regulate the hematopoietic stem cell pool. Increased serum OPN concentrations occur in chronic myeloid leukemia, multiple myeloma, and acute myeloid leukemia (AML). In the present study, we analyzed the prognostic impact of OPN in AML by investigating the expression and relevance of OPN in newly diagnosed AML patients from 2 large study groups (the German AML Cooperative Group and the Dutch-Belgian Hematology Oncology Cooperative group). IHC (n = 84), ELISAs of blood/BM sera (n = 41), and microarray data for mRNA levels (n = 261) were performed. Expression of OPN protein was increased in AML patients both in BM blasts (IHC) and in BM serum (ELISA) compared with healthy controls. Patients expressing high levels of OPN within the BM (IHC) experienced shortened overall survival (OS; P = .025). Multivariate analysis identified karyotype, blast clearance (day 16), and the level of OPN expression as independent prognostic factors for OS. This prompted us to analyze microarray data from 261 patients from a third cohort. The analysis confirmed OPN as a prognostic marker. In summary, high OPN mRNA expression indicated decreased event-free survival (P = .0002) and OS (P = .001). The prognostic role of OPN was most prominent in intermediate-risk AML. These data provide evidence that OPN expression is an independent prognostic factor in AML.


Asunto(s)
Crisis Blástica/metabolismo , Crisis Blástica/mortalidad , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Osteopontina/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Estudios de Cohortes , Supervivencia sin Enfermedad , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia
15.
Am J Hematol ; 86(12): E61-4, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21898532

RESUMEN

There have been several attempts to improve treatment and outcome of patients with primary mediastinal B-cell lymphoma (PMBL) and Burkitt's lymphoma (BL). In recent years, chemotherapy dose intensification and the addition of rituximab have led to a remarkable progress and have developed into integral parts of treatment for both entities of lymphoma [1­4]. Here, we report our monocenter results of a high-dose methotrexate based alternating regimen with rituximab (B-ALL/NHL 2002 protocol) in 15 patients with PMBL and 28 patients with sporadic BL. Since the early 1980s, protocols of GMALL have been continuously adapted and in the meantime they have become reference treatment for BL and B-ALL in Germany. The latest changes comprised the additional use of rituximab, standardized G-CSF support,implementation of high-dose cytarabine, intrathecal triple therapy,and age-adjusted stratification. Furthermore, we additionally amended supportive care with palifermin as it reduced severity and prevalence of mucositis [5].


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Células B/tratamiento farmacológico , Neoplasias del Mediastino/tratamiento farmacológico , Metotrexato/administración & dosificación , Adulto , Factores de Edad , Anciano , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfoma de Burkitt/patología , Estudios de Cohortes , Femenino , Factor 7 de Crecimiento de Fibroblastos/uso terapéutico , Humanos , Linfoma de Células B/patología , Masculino , Neoplasias del Mediastino/patología , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Persona de Mediana Edad , Mucositis/inducido químicamente , Mucositis/prevención & control , Estadificación de Neoplasias , Rituximab , Análisis de Supervivencia , Adulto Joven
17.
PLoS One ; 5(4): e10038, 2010 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-20386613

RESUMEN

BACKGROUND: Falciparum Malaria, an infectious disease caused by the apicomplexan parasite Plasmodium falciparum, is among the leading causes of death and morbidity attributable to infectious diseases worldwide. In Gabon, Central Africa, one out of four inpatients have severe malarial anemia (SMA), a life-threatening complication if left untreated. Emerging drug resistant parasites might aggravate the situation. This case control study investigates biomarkers of enhanced hemolysis in hospitalized children with either SMA or mild malaria (MM). METHODS AND FINDINGS: Ninety-one children were included, thereof 39 SMA patients. Strict inclusion criteria were chosen to exclude other causes of anemia. At diagnosis, erythrophagocytosis (a direct marker for extravascular hemolysis, EVH) was enhanced in SMA compared to MM patients (5.0 arbitrary units (AU) (interquartile range (IR): 2.2-9.6) vs. 2.1 AU (IR: 1.3-3.9), p<0.01). Furthermore, indirect markers for EVH, (i.e. serum neopterin levels, spleen size enlargement and monocyte pigment) were significantly increased in SMA patients. Markers for erythrocyte ageing, such as CD35 (complement receptor 1), CD55 (decay acceleration factor) and phosphatidylserine exposure (annexin-V-binding) were investigated by flow cytometry. In SMA patients, levels of CD35 and CD55 on the red blood cell surface were decreased and erythrocyte removal markers were increased when compared to MM or reconvalescent patients. Additionally, intravascular hemolysis (IVH) was quantified using several indirect markers (LDH, alpha-HBDH, haptoglobin and hemopexin), which all showed elevated IVH in SMA. The presence of both IVH and EVH predicted the need for blood transfusion during antimalarial treatment (odds ratio 61.5, 95% confidence interval (CI): 8.9-427). Interestingly, this subpopulation is characterized by a significantly lowered reticulocyte production index (RPI, p<0.05). CONCLUSIONS: Our results show the multifactorial pathophysiology of SMA, whereby EVH and IVH play a particularly important role. We propose a model where removal of infected and non-infected erythrocytes of all ages (including reticulocytes) by EVH and IVH is a main mechanism of SMA. Further studies are underway to investigate the mechanism and extent of reticulocyte removal to identify possible interventions to reduce the risk of SMA development.


Asunto(s)
Anemia/etiología , Transfusión Sanguínea , Hemólisis , Malaria/patología , Reticulocitos/citología , Anemia/terapia , Biomarcadores , Estudios de Casos y Controles , Niño , Envejecimiento Eritrocítico , Humanos , Malaria/sangre , Malaria/terapia , Plasmodium falciparum , Índice de Severidad de la Enfermedad
18.
Recent Results Cancer Res ; 180: 51-81, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20033378

RESUMEN

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. VEGF gene transcription is induced in particular in hypoxic cells. In developmental angiogenesis, the role of VEGF is demonstrated by the finding that the loss of a single VEGF allele results in defective vascularization and early embryonic lethality. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Platelet-derived growth factor (PDGF) is mainly believed to be an important mitogen for connective tissue, and also has important roles during embryonal development. Its overexpression has been linked to different types of malignancies. Thus, it is important to understand the physiology of VEGF and PDGF and their receptors as well as their roles in malignancies in order to develop antiangiogenic strategies for the treatment of malignant disease.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias/etiología , Factor de Crecimiento Derivado de Plaquetas/fisiología , Receptores del Factor de Crecimiento Derivado de Plaquetas/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Humanos , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/química , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/clasificación
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