Assuntos
Leucemia Mieloide Aguda , Proteína Tumoral p73 , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Prognóstico , Proteína Tumoral p73/genética , Proteína Tumoral p73/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Idoso , Regulação Leucêmica da Expressão Gênica , AdultoRESUMO
Although hematologic neoplasms have been on the vanguard of cancer therapies that led to notable advances in therapeutic efficacy, many patients face significant symptom burden, which make them eligible for early palliative care (PC) integration. However, previous reports demonstrated that hematological malignancies receive more aggressive care at the end-of-life and are less likely to receive care from specialist palliative services compared to solid tumors. Our aim was to characterize symptom burden, performance status and clinical characteristics of a cohort of hematologic malignancies patients referred to PC outpatient consultation, according to their diagnosis. Fifty-nine hematological malignancies patients referred to PC consultation between January 2018 and September 2021 were included. Clinical and laboratory data were evaluated retrospectively by medical charts analysis. Patients exhibited high ESAS and reduced PPS scores at the time of PC referral. Acute leukemia and multiple myeloma patients had the highest symptom burden scores; in spite of this, median time from the first PC consultation until death was only 3 and 4 months, respectively. In conclusion, we identified that hematologic neoplasms patients are highly symptomatic and are frequently referred to PC in end stages of their disease.
Assuntos
Neoplasias Hematológicas , Mieloma Múltiplo , Neoplasias , Humanos , Estudos Retrospectivos , Neoplasias Hematológicas/terapia , Neoplasias/terapia , Cuidados Paliativos , Encaminhamento e Consulta , Mieloma Múltiplo/terapiaAssuntos
Anemia Falciforme , Doenças Vasculares , Anemia Falciforme/complicações , Humanos , NeutrófilosRESUMO
Flavonoids are ubiquitous groups of polyphenolic compounds present in most natural products and plants. These substances have been shown to have promising chemopreventive and chemotherapeutic properties with multiple target interactions and multiple pathway regulations against various human cancers. Polyphenolic flavonoid compounds can block the initiation or reverse the promotion stage of multistep carcinogenesis. Quercetin is one of the most abundant flavonoids found in fruits and vegetables and has been shown to have multiple properties capable of reducing cell growth in cancer cells. Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) therapy remains a challenge for hematologists worldwide, and the outcomes for patients with both disorders continue to be poor. This scenario indicates the increasing demand for innovative drugs and rational combinative therapies. Herein, we discuss the multitarget effects of the flavonoid quercetin, a naturally occurring flavonol, on AML and MDS.
Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Quercetina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicas/metabolismo , Quercetina/química , Quercetina/farmacologia , Espécies Reativas de OxigênioRESUMO
Green tea (GT) treatment was evaluated for its effect on the immune and antineoplastic response of elderly acute myeloid leukemia patients with myelodysplasia-related changes (AML-MRC) who are ineligible for aggressive chemotherapy and bone marrow transplants. The eligible patients enrolled in the study (n = 10) received oral doses of GT extract (1000 mg/day) alone or combined with low-dose cytarabine chemotherapy for at least 6 months and/or until progression. Bone marrow (BM) and peripheral blood (PB) were evaluated monthly. Median survival was increased as compared to the control cohort, though not statistically different. Interestingly, improvements in the immunological profile of patients were found. After 30 days, an activated and cytotoxic phenotype was detected: GT increased total and naïve/effector CD8+ T cells, perforin+/granzyme B+ natural killer cells, monocytes, and classical monocytes with increased reactive oxygen species (ROS) production. A reduction in the immunosuppressive profile was also observed: GT reduced TGF-ß and IL-4 expression, and decreased regulatory T cell and CXCR4+ regulatory T cell frequencies. ROS levels and CXCR4 expression were reduced in bone marrow CD34+ cells, as well as nuclear factor erythroid 2-related factor 2 (NRF2) and hypoxia-inducible factor 1α (HIF-1α) expression in biopsies. Immune modulation induced by GT appears to occur, regardless of tumor burden, as soon as 30 days after intake and is maintained for up to 180 days, even in the presence of low-dose chemotherapy. This pilot study highlights that GT extracts are safe and could improve the immune system of elderly AML-MRC patients.
Assuntos
Leucemia Mieloide Aguda , Chá , Idoso , Linfócitos T CD8-Positivos , Citarabina , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Projetos PilotoRESUMO
Chronic myeloid leukemia (CML) is successfully treated with BCR-ABL1 tyrosine kinase inhibitors, but a significant percentage of patients develop resistance. Insulin receptor substrate 1 (IRS1) has been shown to constitutively associate with BCR-ABL1, and IRS1-specific silencing leads to antineoplastic effects in CML cell lines. Here, we characterized the efficacy of NT157, a pharmacological inhibitor of IGF1R-IRS1/2, in CML cells and observed significantly reduced cell viability and proliferation, accompanied by induction of apoptosis. In human K562 cells and in murine Ba/F3 cells, engineered to express either wild-type BCR-ABL1 or the imatinib-resistant BCR-ABL1T315I mutant, NT157 inhibited BCR-ABL1, IGF1R, IRS1/2, PI3K/AKT/mTOR, and STAT3/5 signaling, increased CDKN1A, FOS and JUN tumor suppressor gene expression, and reduced MYC and BCL2 oncogenes. NT157 significantly reduced colony formation of human primary CML cells with minimal effect on normal hematopoietic cells. Exposure of primary CML cells harboring BCR-ABL1T315I to NT157 resulted in increased apoptosis, reduced cell proliferation and decreased phospho-CRKL levels. In conclusion, NT157 has antineoplastic effects on BCR-ABL1 leukemogenesis, independent of T315I mutational status.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas Substratos do Receptor de Insulina/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirogalol/análogos & derivados , Receptor IGF Tipo 1/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Humanos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Pirogalol/farmacologia , Pirogalol/uso terapêutico , Sulfonamidas/farmacologiaRESUMO
LEF1 antisense RNA 1 (LEF1-AS1) is an antisense long non-coding RNA encoded in the lymphoid enhancer-binding factor 1 (LEF1) locus. LEF1-AS1 is a conserved transcript dysregulated in hematopoiesis. This study aimed to functionally characterize the role of this transcript in myeloid malignancy and explore a possible regulatory effect of LEF1-AS1 upon LEF1. We show that LEF1-AS1 is highly expressed in normal hematopoietic stem cells but barely detectable in myeloid malignant cell lines. Additionally, bone marrow cells from myelodysplastic syndrome (n=12) and acute myeloid malignancy patients (n=28) expressed significantly reduced levels of LEF1-AS1 compared to healthy controls (n=15). Artificial LEF1-AS1 over-expression inhibited proliferation in HL60 and led to an upregulation of tumor suppressors p21 and p27, and reduced ERK1/2 activation. Unexpectedly, no underlying modulation of LEF1 was detected. Ectopic expression of LEF1-AS1 also inhibited proliferation in HELA, a cell line lacking endogenous expression of LEF1, supporting a LEF1-independent mechanism. Additionally, transient over-expression of LEF1-AS1 in AML patient cells also led to reduced proliferation and colony formation capacity. We used a mass spectrometry-based proteomics approach. Proteomic quantification identified the modulation of an important metabolic regulator, Fumarase, and concomitant accumulation of the metabolite fumarate.
Assuntos
Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/patologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Síndromes Mielodisplásicas/patologia , RNA Longo não Codificante/genética , Estudos de Casos e Controles , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Prognóstico , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
Disturbances in the physiological regulation of erythropoietin (EPO) in patients with sickle cell disease (SCD) may contribute to worsening anaemia and increased transfusion requirements, but the use of recombinant EPO in this group of patients is controversial. The objective of this study was to evaluate the use of this drug in adult patients with SCD and its effects on haemoglobin levels and transfusion requirements. We conducted a retrospective analysis at the University of Campinas, with nineteen adults with a diagnosis of SCD (HbSS and HbS/ß+ thalassaemia), who had received at least 1 year of EPO therapy between 2007 and 2014. Haemoglobin concentrations and trends of variation in transfused RBC volumes were compared before and after EPO administration. We observed that seven patients had a good response to treatment (Hb increment higher than 1·5 g/dl) and nine had a partial response (0·5-1·5 g/dl increment) and there was a significant decrease in the need for transfusion amongst those who usually required regular transfusions. There were no increases in the rates of vaso-occlusive crisis or venous thromboembolism in comparison to the year before the onset of the therapy. Erythropoietin therapy led to a marked increase in haemoglobin concentration with a concomitant decrease in the demand for transfusion. Considering all complications related to allogeneic transfusion, we believe that EPO therapy represents an important therapeutic tool in sickle cell anaemia.
Assuntos
Anemia Falciforme/tratamento farmacológico , Eritropoetina/uso terapêutico , Adulto , Anemia Falciforme/terapia , Transfusão de Eritrócitos/efeitos adversos , Eritropoetina/administração & dosagem , Feminino , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêuticoRESUMO
In this study, we describe four new patients with sickle cell disease who had limb amputations. Two of the patients had sickle cell anemia [Hb S (HBB: c.20A > T) (ß(S)/ß(S))] with refractory leg ulcers that required amputations. The third patient had sickle cell trait with an extensive leg ulcer that was associated with epidermoid carcinoma. The fourth patient had amputations of both forearms and feet due to a misdiagnosis of dactylitis. Review of the literature showed that the indications for amputations in sickle cell disease included three distinct categories: mythical beliefs, therapeutic and malpractice. All therapeutic amputations were for severely painful, large, recalcitrant leg ulcers that failed non-interventional therapies. Amputation resulted in pain relief and better quality of life. Phantom neuropathic pain was not a major issue post-operatively. It was absent, transient or well controlled with antidepressants. Limb function was restored post-amputation with prosthetic artificial limbs, wheelchairs or crutches. Malpractice amputations were due to misdiagnosis or to cryotherapy by exposing the painful limb to ice water resulting in thrombosis, gangrene and amputation. We strongly suggest that leg amputations should be considered in the management of certain patients with severe extensive refractory leg ulcers, and topical cryotherapy should never be used to manage sickle cell pain.
Assuntos
Amputação Cirúrgica , Anemia Falciforme/cirurgia , Úlcera da Perna/cirurgia , Qualidade de Vida , Anemia Falciforme/complicações , Anemia Falciforme/terapia , Tomada de Decisões , Erros de Diagnóstico , Humanos , Úlcera da Perna/etiologia , Imperícia , Manejo da DorRESUMO
The recurrent V617F mutation in JAK2 (JAK2V617F) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indicates the need for identifying pathways that cooperate with JAK2. Activated JAK2 was found to be associated with the insulin receptor substrate 2 (IRS2) in non-hematological cells. We identified JAK2/IRS2 binding in JAK2V617F HEL cells, but not in the JAK2WT U937 cell line. In HEL cells, IRS2 silencing decreased STAT5 phosphorylation, reduced cell viability and increased apoptosis; these effects were enhanced when IRS2 silencing was combined with ruxolitinib. In U937 cells, IRS2 silencing neither reduced cell viability nor induced apoptosis. IRS1/2 pharmacological inhibition in primary MPN samples reduced cell viability in JAK2V617F-positive but not JAK2WT specimens; combination with ruxolitinib had additive effects. IRS2 expression was significantly higher in CD34+ cells from essential thrombocythemia patients compared to healthy donors, and in JAK2V617F MPN patients when compared to JAK2WT. Our data indicate that IRS2 is a binding partner of JAK2V617F in MPN. IRS2 contributes to increased cell viability and reduced apoptosis in JAK2-mutated cells. Combined pharmacological inhibition of IRS2 and JAK2 may have a potential clinical application in MPN.