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INTRODUCTION: Therapeutic adherence (TA) is one of the most important factors influencing the effectiveness of treatment. Oral anti-cancer drugs are increasingly used to treat malignancy including multiple myeloma (MM). Our study aimed to determine TA of patients with MM treated with IMiDs, to identify TA risk factors, and to determine satisfaction with medical care during the treatment with IMiDs. METHODS: A cross-sectional survey-based study involving adult patients with MM treated with IMiDs. RESULTS: Between January 2021 and May 2021, 267 patients with MM were enrolled in the study. The dosing schedule was declared as easy by 71.8% of patients, as standard for 24.0%, and difficult for 4.2% of patients. During MM treatment, 85.0% of patients did not skip any IMiDs dose, and 87.6% did not skip the IMiDs dose in the last cycle of chemotherapy. Identified factors affecting TA included the treatment duration and education level. In addition, depending on the patient's well-being, gender, and household companionship influenced TA. Satisfaction with medical care during the treatment with IMiDs was declared by 95.5% of patients with MM. In our cohort, 95.5% of patients were satisfied with the information they received from the hematologist during treatment with IMiDs. CONCLUSIONS: Patients with MM treated with IMiDs are highly adherent to treatment. With time from the beginning of treatment, patients need more attention and motivation to adhere to the therapy rules.
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The pathophysiology of the severe course of COVID-19 is multifactorial and not entirely elucidated. However, it is well known that the hyperinflammatory response and cytokine storm are paramount events leading to further complications. In this paper, we investigated the vascular response in the pathophysiology of severe COVID-19 and aimed to identify novel biomarkers predictive of ICU admission. The study group consisted of 210 patients diagnosed with COVID-19 (age range: 18-93; mean ± SD: 57.78 ± 14.16), while the control group consisted of 80 healthy individuals. We assessed the plasma concentrations of various vascular factors using the Luminex technique. Then, we isolated RNA from blood mononuclear cells and performed a bioinformatics analysis investigating various processes related to vascular response, inflammation and angiogenesis. Our results confirmed that severe COVID-19 is associated with vWF/ADAMTS 13 imbalance. High plasma concentrations of VEGFR and low DPP-IV may be potential predictors of ICU admission. SARS-CoV-2 infection impairs angiogenesis, hinders the generation of nitric oxide, and thus impedes vasodilation. The hypercoagulable state develops mainly in the early stages of the disease, which may contribute to the well-established complications of COVID-19.
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COVID-19 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Inflamação , Unidades de Terapia Intensiva , SARS-CoV-2 , VasodilataçãoRESUMO
It has been postulated that the changes in the molecular characteristics of the malignant clone(s) and the abnormal activation of JAK-STAT signaling are responsible for myeloproliferative neoplasm progression to more advanced disease phases and the immune escape of the malignant clone. The continuous JAK-STAT pathway activation leads to enhanced activity of the promoter of CD274 coding programmed death-1 receptor ligand (PD-L1), increased PD-L1 level, and the immune escape of MPN cells. The aim of study was to evaluate the PDL1 mRNA and JAK2 mRNA level in molecularly defined essential thrombocythaemia (ET) patients (pts) during disease progression to post-ET- myelofibrosis (post-ET-MF). The study group consisted of 162 ET pts, including 30 pts diagnosed with post-ET-MF. The JAK2V617F, CALR, and MPL mutations were found in 59.3%, 19.1%, and 1.2% of pts, respectively. No copy-number alternations of the JAK2, PDL1, and PDCDL1G2 (PDL2) genes were found. The level of PD-L1 was significantly higher in the JAK2V617F than in the JAK2WT, CALR mutation-positive, and triple-negative pts. The PD-L1 mRNA level was weakly correlated with both the JAK2V617F variant allele frequency (VAF), and with the JAK2V617F allele mRNA level. The total JAK2 level in post-ET-MF pts was lower than in ET pts, despite the lack of differences in the JAK2V617F VAF. In addition, the PD-L1 level was lower in post-ET-MF. A detailed analysis has shown that the decrease in JAK2 and PDL1 mRNA levels depended on the bone marrow fibrosis grade. The PDL1 expression showed no differences in relation to the genotype of the JAK2 haplotypeGGCC_46/1, hemoglobin concentration, hematocrit value, leukocyte, and platelet counts. The observed drop of the total JAK2 and PDL1 levels during the ET progression to the post-ET-MF may reflect the changes in the JAK2V617F positive clone proliferative potential and the PD-L1 level-related immunosuppressive effect. The above-mentioned hypothesis is supported by The Cancer Genome Atlas (TCGA) data, confirming a strong positive association between CD274 (encoding PD-L1), CXCR3 (encoding CXCR3), and CSF1 (encoding M-CSF) expression levels, and recently published results documenting a drop in the CXCR3 level and circulating M-CSF in patients with post-ET-MF.
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Transtornos Mieloproliferativos , Mielofibrose Primária , Trombocitemia Essencial , Humanos , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Janus Quinases/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Mutação , RNA Mensageiro/genética , Calreticulina/genética , Calreticulina/metabolismoRESUMO
Abnormalities in hematological parameters of peripheral blood have been noted in patients with endogenous Cushing's Syndrome (CS) in the corticotropin (ACTH)-dependent and ACTH-independent forms. Nevertheless, the exact mechanism of glucocorticoids (GCs) action on human hematopoiesis is still not entirely clear. The aim of the study was to determine whether endogenous excessive production of GCs could affect apoptosis of CD34+ cells enriched in hematopoietic stem and progenitor cells (HSPCs) collected from the peripheral blood of newly diagnosed CS patients. Flow cytometry, Annexin-V enzyme-linked immunosorbent assay, TUNEL assay, real-time quantitative PCR, and microarray RNA/miRNA techniques were used to characterize CS patients' HSPCs. We found that the glucocorticoid receptor (GR) protein expression levels in CS were higher than in healthy controls. A complex analysis of apoptotic status of CS patients' HSPC cells showed that GCs significantly augmented apoptosis in peripheral blood-derived CD34+ cells and results obtained using different methods to detect early and late apoptosis in analyzed cell population were consistent. CS was also associated with significant upregulation in several members of the BCL-2 superfamily and other genes associated with apoptosis control. Furthermore, global gene expression analysis revealed significantly higher expression of genes associated with programmed cell death control in HSPCs from CS patients. These findings suggest that human endogenous GCs have a direct pro-apoptotic activity in hematopoietic CD34+ cells derived from CS subjects before treatment.
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Síndrome de Cushing , Glucocorticoides , Humanos , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Síndrome de Cushing/metabolismo , Antígenos CD34/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Apoptose/fisiologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Hormônio Adrenocorticotrópico/metabolismoRESUMO
The exact pathophysiology of severe COVID-19 is not entirely elucidated, but it has been established that hyperinflammatory responses and cytokine storms play important roles. The aim of this study was to examine CMV status, select chemokines, and complement components in COVID-19, and how concentrations of given molecules differ over time at both molecular and proteomic levels. A total of 210 COVID-19 patients (50 ICU and 160 non-ICU patients) and 80 healthy controls were enrolled in this study. Concentrations of select chemokines (CXCL8, CXCL10, CCL2, CCL3, CCR1) and complement factors (C2, C9, CFD, C4BPA, C5AR1, CR1) were examined at mRNA and protein levels with regard to a COVID-19 course (ICU vs. non-ICU group) and CMV status at different time intervals. We detected several significant differences in chemokines and complement profiles between ICU and non-ICU groups. Pro-inflammatory chemokines and the complement system appeared to greatly contribute to the pathogenesis and development of severe COVID-19. Higher concentrations of CXCL8 and CCL2 in the plasma, with reduced mRNA expression presumably through negative feedback mechanisms, as well as CMV-positive status, correlated with more severe courses of COVID-19. Therefore, CXCL8, CCL2, and CMV seropositivity should be considered as new prognostic factors for severe COVID-19 courses. However, more in-depth research is needed.
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COVID-19 , Infecções por Citomegalovirus , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Infecções por Citomegalovirus/complicações , Humanos , Prognóstico , Proteômica , RNA MensageiroRESUMO
We present a unique case of a young woman with acute myeloid leukemia (AML) with complex karyotype. The presence of the t(4;11)(q23;p15) is extremely rare in myeloid leukemias, while t(4;8)(q32;q13) has not yet been described in any leukemia reference. Another interesting issue is the familial aggregation of myeloid malignancies and worse course of the disease in each subsequent generation, as well as an earlier onset of the disease. Our report emphasizes the need for thorough pedigree examination upon myeloid malignancy diagnosis as there are relatives for whom counseling, gene testing, and surveillance may be highly advisable.
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Leucemia Mieloide Aguda , Translocação Genética , Feminino , Humanos , Cariótipo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , LinhagemRESUMO
We present an extremely rare case report of a 29-year-old multiple myeloma patient with central nervous system involvement and secondary hemophagocytic lymphohistiocytosis (HLH). We observed that HLH was presumably triggered by the immunomodulatory drug-lenalidomide. HLH is frequently misdiagnosed or underdiagnosed. As HLH requires immediate treatment, our report emphasizes the need to consider HLH in the differential diagnosis when the condition of a patient receiving chemotherapy rapidly deteriorates and an infectious etiology is excluded. We furthermore discuss the pathogenesis of HLH, with particular emphasis on drugs affecting the immune system as well as possible therapeutic strategies.
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Linfo-Histiocitose Hemofagocítica , Mieloma Múltiplo , Segunda Neoplasia Primária , Humanos , Adulto , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida/uso terapêutico , Agentes de Imunomodulação , Diagnóstico DiferencialRESUMO
Chronological skin ageing is an inevitable physiological process that results in thin and sagging skin, fine wrinkles, and gradual dermal atrophy. The main therapeutic approaches to soft tissue augmentation involve using dermal fillers, where natural fillers, such as autologous fibroblasts, are involved in generating dermal matrix proteins. The aim of this study was to determine the global transcriptome profile of three passages of dermal autologous fibroblasts from a male volunteer, focusing on the processes of the cell cycle and cell proliferation status to estimate the optimal passage of the tested cells with respect to their reimplantation. We performed K-means clustering and validation of the expression of the selected mRNA by qRT-PCR. Ten genes were selected (ANLN, BUB1, CDC20, CCNA2, DLGAP5, MKI67, PLK1, PRC1, SPAG5, and TPX2) from the top five processes annotated to cluster 5. Detailed microarray analysis of the fibroblast genes indicated that the cell population of the third passage exhibited the highest number of upregulated genes involved in the cell cycle and cell proliferation. In all cases, the results of qRT-PCR confirmed the differences in expression of the selected mRNAs between fibroblasts from the primary culture (C0) and from the first (C1), second (C2), and third (C3) cell passage. Our results thus suggest that these cells might be useful for increasing fibroblast numbers after reimplantation into a recipient's skin, and the method used in this study seems to be an excellent tool for autologous transplantation allowing the rejuvenation of aging skin.
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Técnicas Cosméticas , Fibroblastos/fisiologia , Envelhecimento da Pele/genética , Pele/citologia , Ciclo Celular/genética , Proliferação de Células/genética , Células Cultivadas , Face , Fibroblastos/transplante , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Reação em Cadeia da Polimerase em Tempo Real , Rejuvenescimento , Transplante Autólogo/métodosRESUMO
We present one of few cases of COVID-19 occurrence during the early phase of autologous hematopoietic stem cell transplantation. We observed an interesting correlation between the patient's rapid clinical deterioration and myeloid reconstitution that cannot be assigned to engraftment syndrome. Our report emphasizes the need to investigate whether timely steroid therapy upon neutrophil engraftment in the setting of COVID-19 could limit the extent of lung injury and prevent ARDS. Furthermore, we discuss a significant issue of possible prolonged incubation of the virus in heavily pretreated hematological patients.
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COVID-19 , Transplante de Células-Tronco Hematopoéticas , Humanos , SARS-CoV-2 , Transplante AutólogoRESUMO
Introduction: Regenerative capacity of the heart is limited, and the post-infarct left ventricle (LV) dysfunction is associated with poor prognosis. Administration of stem/progenitor cells (SPCs) is a promising approach for cardiac regeneration. Objectives: In the study, we assessed LV function and post-infarcted remodeling in patients with ST-elevated myocardial infarct (STEMI) who received autologous lineage-negative (LIN-) SPCs. Patients and methods: Patients with STEMI and one-vessel coronary artery disease treated with percutaneous revascularisation were divided into study group (LIN- group, 15 patients) that received standard therapy and autologous BM-derived LIN- SPCs and control group (standard therapy group, 19 patients). The cells were administered intracoronary 24 hours after STEMI. The follow-up was 12 months with subsequent non-invasive tests and laboratory parameter evaluation on days 1st, 3rd, and 7th as well as at 1st, 3rd, 6th and 12th month after STEMI. Results: All procedures related to SPCs administration were well tolerated by the patients. In 12-month follow-up, there were no major adverse cardiac events connected with LIN- SPCs administration. During 12-month follow-up, 9 patients from LIN- group (Responders) achieved an improvement in LV ejection fraction (>10% after 12 months) with no signs of unfavorable LV remodeling. Laboratory parameters analysis showed that Troponin T levels were significantly lower until day 7th in the Responders group, while brain natriuretic peptide (BNP) level remained significantly lower from day 3rd to 12th month respectively. Conclusions: Intracoronary infusion of autologous BM-derived LIN- stem/progenitor cells is feasible and safe for patient. Improvement in LV function and prevention of unfavorable remodeling in the 60% of study group seems relatively promising. Stem cell-based therapy for cardiac regeneration still needs more accurate and extensive investigations to estimate and improve their efficacy.
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Doença da Artéria Coronariana/terapia , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Transplante de Células-Tronco/métodos , Remodelação Ventricular/fisiologia , Adulto , Terapia Combinada/métodos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários , Feminino , Seguimentos , Humanos , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Transplante Autólogo/métodos , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
Bortezomib is an anti-tumor agent, which inhibits 26S proteasome degrading ubiquitinated proteins. While apoptotic transcription-associated activation in response to bortezomib has been suggested, mechanisms related to its influence on post-transcriptional gene silencing mediated regulation by non-coding RNAs remain not fully elucidated. In the present study, we examined changes in global gene and miRNA expression and analyzed the identified miRNA-mRNA interactions after bortezomib exposure in human neuroblastoma cells to define pathways affected by this agent in this type of cells. Cell viability assays were performed to assess cytotoxicity of bortezomib. Global gene and miRNA expression profiles of neuroblastoma cells after 24-h incubation with bortezomib were determined using genome-wide RNA and miRNA microarray technology. Obtained results were then confirmed by qRT-PCR and Western blot. Further bioinformatical analysis was performed to identify affected biological processes and pathways. In total, 719 genes and 28 miRNAs were downregulated, and 319 genes and 61 miRNAs were upregulated in neuroblastoma cells treated with bortezomib. Possible interactions between dysregulated miRNA/mRNA, which could be linked to bortezomib-induced neurotoxicity, affect neurogenesis, cellular calcium transport, and neuron death. Bortezomib might exert toxic effects on neuroblastoma cells and regulate miRNA-mRNA interactions influencing vital cellular functions. Further studies on the role of specific miRNA-mRNA interactions are needed to elucidate mechanisms of bortezomib action.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bortezomib/farmacologia , MicroRNAs/metabolismo , Neuroblastoma/metabolismo , RNA Mensageiro/metabolismo , Apoptose/genética , Cálcio/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Biologia Computacional , Regulação para Baixo , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , MicroRNAs/genética , Análise em Microsséries , Neuroblastoma/genética , Neurogênese/genética , RNA Mensageiro/genética , Regulação para CimaRESUMO
Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin-) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin- cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations.
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Esclerose Lateral Amiotrófica/terapia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína C-Reativa/metabolismo , MicroRNAs/sangue , MicroRNAs/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/imunologia , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/líquido cefalorraquidiano , Proteína C-Reativa/líquido cefalorraquidiano , Linhagem da Célula , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunidade Humoral , Injeções Espinhais , MicroRNAs/líquido cefalorraquidiano , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Transplante de Células-TroncoRESUMO
Background and objectives: Speech disorders are observed in 30% of newly diagnosed sporadic amyotrophic lateral sclerosis (ALS) patients. Characterized by a dynamic course, dysfunction of articulation has not so far been well understood. The aim of this study was to analyze the influence of demographic factors (sex, age, duration of the disease) and concomitant diseases (degenerative spine disease, depression, hypertension, hypothyroidism, hyperthyroidism, and allergy) on the functioning of speech organs in ALS patients. Materials and Methods: The study group consisted of 65 patients with sporadic ALS. Patients were examined for articulatory functions by means of the Frenchay Dysarthria Assessment (FDA). Results: 68% of the study sample had spinal disorders. Logistic regression analysis showed that a decline in the functioning of lips, soft palate, length of phonation, and voice loudness was more common among men. Patients diagnosed with degenerative spine disease more often suffered from respiratory disorders, while younger patients (<60 years of age) significantly more often had the impairment of the sentence and spontaneous speech functions. Conclusions: The male gender in patients with ALS is associated with an increased risk of deterioration of the phonation length function. Patients under 60 years of age are associated with more often pronouncing sentences disorders and spontaneous speech disorders.
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Esclerose Lateral Amiotrófica/complicações , Escores de Disfunção Orgânica , Distúrbios da Fala/etiologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/fisiopatologia , Comorbidade , Demografia/métodos , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of a rapid course. In 25% of ALS sufferers, speech disorders occur as prodromal symptoms of the disease. Impaired communication affects physical health and has a negative impact on mental and emotional condition. In this study, we assessed which domains of speech are particularly affected in ALS. Subsequently, we estimated possible correlations between the ALS patients' subjective perception of their speech quality and an objective assessment of the speech organs carried out by an expert. METHODS: The study group consisted of 63 patients with sporadic ALS. The patients were examined for articulatory functions by means of Voice Handicap Index (VHI) and the Frenchay Dysarthria Assessment (FDA). RESULTS: On the basis of the VHI scores, the entire cohort was divided into 2 groups: group I (40 subjects) with mild speech impairment, and group II (23 subjects) displaying moderate and profound speech deficits. In an early phase of ALS, changes were typically reported in the tongue, lips and soft palate. The FDA and VHI-based measurements revealed a high, positive correlation between the objective and subjective evaluation of articulation quality. CONCLUSIONS: Deterioration of the articulatory organs resulted in the reduction of social, physical and emotional functioning. The highly positive correlation between the VHI and FDA scales seems to indicate that the VHI questionnaire may be a reliable, self-contained tool for monitoring the course and progression of speech disorders in ALS. TRIAL REGISTRATION: NCT02193893 .
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Esclerose Lateral Amiotrófica/complicações , Distúrbios da Fala/diagnóstico , Distúrbios da Fala/etiologia , Patologia da Fala e Linguagem/métodos , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fala/fisiologiaRESUMO
Cell therapy raises hope to reduce the harmful effects of acute myocardial ischemia. Stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed the plasma levels of selected trophic factors in patients undergoing application of autologous bone marrow (BM)-derived, lineage-negative (Lin-) stem/progenitor cells into the coronary artery in the acute phase of myocardial infarction. The study group consisted of 15 patients with acute myocardial infarction (AMI) who underwent percutaneous revascularization and, afterwards, Lin- stem/progenitor cell administration into the infarct-related artery. The control group consisted of 19 patients. BM Lin- cells were isolated using immunomagnetic methods. Peripheral blood was collected on day 0, 2, 4, and 7 and after the first and third month to assess the concentration of selected trophic factors using multiplex fluorescent bead-based immunoassays. We found in the Lin- group that several angiogenic trophic factors (vascular endothelial growth factor, Angiopoietin-1, basic fibroblast growth factor, platelet-derived growth factor-aa) plasma level significantly increased to the 4th day after myocardial infarction. In parallel, we noticed a tendency where the plasma levels of the brain-derived neurotrophic factor were increased in the Lin- group. The obtained results suggest that the administered SPCs may be a valuable source of angiogenic trophic factors for damaged myocardium, although this observation requires further in-depth studies.
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Indutores da Angiogênese/sangue , Linhagem da Célula , Vasos Coronários/patologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/terapia , Transplante de Células-Tronco , Células-Tronco/citologia , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado de Linhagem de Célula Glial/sangue , Humanos , Pessoa de Meia-IdadeRESUMO
Growth hormone (GH) modulates hematopoietic cell homeostasis and is associated with apoptosis control, but with limited mechanistic insights. Aim of the study was to determine whether GH therapeutic supplementation (GH-TS) could affect apoptosis of CD34+ cells enriched in hematopoietic progenitor cells of GH deficient (GHD) children. CD34+ cells from peripheral blood of 40 GHD children were collected before and in 3rd and 6th month of GH-TS and compared to 60 controls adjusted for bone age, sex, and pubertal development. Next, apoptosis assessment via different molecular techniques was performed. Finally, to comprehensively characterize apoptosis process, global gene expression profile was determined using genome-wide RNA microarray technology. Results showed that GH-TS significantly reduced spontaneous apoptosis in CD34+ cells (p < 0.01) and results obtained using different methods to detect early and late apoptosis in analyzed cells population were consistent. GH-TS was also associated with significant downregulation of several members of TNF-alpha superfamily and other genes associated with apoptosis and stress response. Moreover, the significant overexpression of cyto-protective and cell cycle-associated genes was detected. These findings suggest that recombinant human GH has a direct anti-apoptotic activity in hematopoietic CD34+ cells derived from GHD subjects in course of GH-TS.
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Antígenos CD34/metabolismo , Hormônio do Crescimento/deficiência , Hormônio do Crescimento/fisiologia , Células-Tronco Hematopoéticas/patologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Contagem de Células , Criança , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Masculino , Receptores da Somatotropina/metabolismoRESUMO
AIM: The relationship between ischemic vascular disease and age-related macular degeneration may indicate the role of vascular injury as the primary insult causing functional deficits in age-related macular degeneration. The vasoactive factors produced by endothelial cells include endothelin-1 (ET-1), which is one of the most potent vasoconstricting peptides. In this study we sought to explore the potential role of endothelial dysfunction in the pathogenesis of age-related macular degeneration by measuring the concentration of ET-1 in peripheral blood of individuals diagnosed with age-related macular degeneration and evaluating its intracellular expression in peripheral blood cells, on mRNA level. MATERIAL AND METHODS: Peripheral blood samples from 31 patients with diagnosed dry age-related macular degeneration and 46 patients with neovascular age-related macular degeneration were collected. Forty six age- and sex-matched volunteers without age-related macular degeneration were enrolled as a control group. ET-1 plasma levels were analyzed by ELISA and intracellular expression of ET-1 in peripheral blood cells was studied by using qRT-PCR. RESULTS: The expression of intracellular ET-1 was significantly elevated in peripheral blood cells of both dry and wet age-related macular degeneration patients compared with the control subjects. Immunofluorescence staining revealed that ET-1 was specifically expressed in the circulating endothelial cells. CONCLUSIONS: We assume that damaged endothelial cells may release a variety of vasoconstricting molecules, including ET-1, leading to derangement between the endothelium-derived relaxing and contracting factors. Local retinal ischemia consequently develops which may promote the development of retinal degeneration in patients with age-related macular degeneration,
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Endotelina-1/sangue , Degeneração Macular/sangue , Degeneração Macular/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Diagnóstico Precoce , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Background and Objectives: The effective treatment of chronic myeloid leukemia leads to the restoration of proper immune system function. We aimed to investigate fluctuations in circulating cytokines, angiogenic factors and complement components in patients with CML during the first year of treatment with TKI and correlate them with the degree of achieved molecular response. Material and Methods: We recruited 31 patients with newly diagnosed CML. Peripheral blood and bone marrow samples were obtained, and concentrations of serum proteins were measured using an immunology multiplex assay. Results: The study cohort was divided into two groups of optimal or non-optimal in accordance with the European Leukemia Net (ELN) guidelines. We found significantly higher concentrations of C1q, C4 and C5a in serum after 3 months of TKI treatment in patients who achieved optimal responses in the 6 months after diagnosis. The most alterations were observed during 12 months of therapy. Patients in the optimal response group were characterized by higher serum concentrations of TGF-ß, EGF, VEGF, Angiopoietin 1, IFN-γ and IL-8. Conclusions: The later plasma concentrations of complement components were significantly increased in patients with optimal responses. The changes after 12 months of treatment were particularly significant. Similar changes in bone marrow samples were observed.
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Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/uso terapêutico , Prognóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Antineoplásicos/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas de Membrana Transportadoras/uso terapêutico , Resultado do TratamentoRESUMO
Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.