Immune Dysregulation in Myelodysplastic Syndromes: Pathogenetic-Pathophysiologic Aspects and Clinical Consequences

Myelodysplastic syndromes are clonal hematopoietic stem cell disorders, in which the immune system plays a substantial pathogenetic role. Patients manifest frequent infections, mainly attributed to neutropenia, but sometimes opportunistic pathogens are isolated in non-neutropenic patients. They also exhibit autoimmune diseases or syndromes with a background of immune activation and various “abnormalities” of T-lymphocytes, B-lymphocytes, and NK cells. The most typical profile includes reduced total T lymphocytes (mainly CD4+ helper T-cells, resulting in decrease or inversion of the CD4/CD8 cell ratio) and impaired NK cell function. Many TH1 direction cytokines, and particularly sIL-2R, IL-6, and TNF-α are usually found increased in the serum and bone marrow, which have been strongly associated with advanced disease, anemia, and other disease-related features. Clonal origin of lymphocytes has been confirmed only in few cases. Mixed lymphocyte cultures and genomic assays have shown severely impaired immunoregulatory abnormalities, probably induced by the hematopoietic cells. In a minority of patients, immune activation is capable to prevent or delay clonal expansion, but these patients have more profound hematopoietic impairment. Immunosuppressive treatment may not only relieve the autoimmune manifestations but also improve hematopoiesis. However, this kind of treatment is not well tolerated, is associated with severe infections, and in some cases may enhance AML evolution

Diagnostic and prognostic utility of serum receptor-binding cancer antigen expressed on SiSo cells (RCAS1) levels in colon cancer patients

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that induces cell-cycle arrest and/or apoptosis in cells bearing the RCAS1 receptor. The aim of the present study was to elucidate the diagnostic and prognostic utility of RCAS1 levels in colon cancer patients. Serum RCAS1 levels were determined using a sandwich enzyme-linked immunosorbent assay in 97 colon cancer patients and 20 healthy individuals. The levels were significantly increased in colon cancer patients compared to healthy individuals (p<0.0001). Increased RCAS1 levels were significantly associated with advanced Dukes’ stage (p=0.0079) and high histopathological tumor grade (p=0.0028). Univariate analysis revealed that colon cancer patients with elevated RCAS1 levels had significantly shorter overall survival times (log-rank test, p=0.027). By multivariate analysis, serum RCAS1 was identified as an independent prognostic factor (Cox regression analysis, p=0.033). In conclusion, colon cancer patients with advanced disease stage and grade and poor prognosis showed elevated serum RCAS1 levels. Assessment of serum RCAS1 levels could therefore be considered as a diagnostic and prognostic marker in colon neoplasia. (Int J Rio Markers 2009; 24: 70-6

Serum tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2) levels in colorectal cancer patients: associations with clinicopathological variables and patient survival

Tissue inhibitors of metalloproteinases (TIMPs) appear to affect many aspects of cancer biology, playing a crucial role in cell signaling by regulating cell growth, apoptosis, invasion, metastasis, angiogenesis, and genomic instability. The aim of the present study was to elucidate the diagnostic and prognostic utility of TIMP-1 and TIMP-2 in patients with colon cancer. Serum TIMP-1 and TIMP-2 concentrations were quantified using an enzyme-linked immunosorbent assay in 97 colon cancer patients. Elevated serum TIMP-1 levels were found in patients with advanced disease stage (p=0.0512) and poorly differentiated histopathological tumor grade (p=0.0059). Patients with increased TIMP-1 levels had shorter overall survival times (log-rank test, p=0.0143). Multivariate analysis also identified TIMP-1 as an independent prognostic factor (Cox regression analysis, p=0.0149). Serum TIMP-2 levels were not significantly associated with disease stage, histopathological grade or survival. In the subgroup of patients with well and moderately differentiated tumors, TIMP-1 and TIMP-2 were identified as independent prognostic factors (Cox regression analysis, p=0.0379 and p=0.0451, respectively). In conclusion, assessment of serum TIMP-1 can be considered a useful biomarker in colon cancer, whereas TIMP-2 appears to be of limited value. (Int J Biol Markers 2009; 24: 245-52

Prevalence of anti-HAV antibodies in multitransfused patients with beta-thalassemia

AIM: To detect the prevalence of anti-HAV IgG antibodies in adult multitransfused beta-thalassemic patients

Plasma neutrophil gelatinase-associated lipocalin levels are markedly increased in patients with non-transfusion-dependent thalassemia: Lack of association with markers of erythropoiesis, iron metabolism and renal function

Background: Neutrophil Gelatinase-Associated Lipocalin (NGAL) (known as NGAL, Lipocalin 2, Siderocalin, Uterocalin, proteinase-3 and 24p3) is a mammalian small 25-kD peptide that belongs to the lipocalin superfamily, which consists of about 20 small lipoproteins. NGAL was initially discovered as an antibacterial factor of natural immunity and an acute-phase protein. NGAL is also an iron trafficking protein, a member of the non-transferrin-bound iron (NTBI) pool and an alternative to the transferrin-mediated iron-delivery pathway. Of note, NTBI, which is elevated in thalassemic patients, induces cellular toxicity. In this study we investigated the possible association of NGAL with parameters of erythropoiesis, iron metabolism and renal injury in patients with non-transfusion-dependent thalassemia (thalassemia intermedia or TI). Patients and methods: Thirty-five patients with TI, 13 men and 22 women, aged 8-63 years, were included in the study, while, 20 healthy individuals served as controls. Plasma NGAL levels were determined using an immunoenzymatic technique. Erythroid marrow activity was estimated by measuring soluble transferrin receptors (sTfR) levels with a turbidimetric technique. NTBI levels were determined using electrothermal atomic absorption spectrometry. Cystatin C, beta 2-microglobulin and hs-CRP concentrations were measured by means of immunonephelometric techniques. Results: The main results of the study showed: a) NGAL levels were significantly higher in patients with TI compared to controls (139.1 +/- 86.1 vs 51.2 +/- 11.8 mu g/L, p < 0.0001), without significant effect of splenectomy or hydroxyurea on NGAL levels. Only 4 patients had NGAL levels within the control group range, b) no correlation was found between NGAL levels and either the parameters of erythropoiesis Hb, Hb F, reticulocytes and sTfR (p > 0.66, p > 0.67, p > 0.63 and p > 0.81 respectively), or with those of iron metabolism ferritin and NTBI (p > 0.90 and p > 0.95 respectively). Conclusions: The increased NGAL levels reported for the first time in TI patients in this study are in agreement with the elevated expression of NGAL observed in TI mouse models. We postulate that the induction of NGAL in these patients may represent either a survival response, facilitating the survival of the less damaged thalassemic erythroid precursors, or a consequence of the abnormal iron regulation in TI. (C) 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved

Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea

Abstract Background We aimed to clarify the emerging epigenetic landscape in a group of genes classified as “modifier genes” of the β-type globin genes (HBB cluster), known to operate in trans to accomplish the two natural developmental switches in globin expression, from embryonic to fetal during the first trimester of conception and from fetal to adult around the time of birth. The epigenetic alterations were determined in adult sickle cell anemia (SCA) homozygotes and SCA/β-thalassemia compound heterozygotes of Greek origin, who are under hydroxyurea (HU) treatment. Patients were distinguished in HU responders and HU non-responders (those not benefited from the HU) and both, and in vivo and in vitro approaches were implemented. Results We examined the CpG islands’ DNA methylation profile of BCL11A, KLF1, MYB, MAP3K5, SIN3A, ZBTB7A, and GATA2, along with γ-globin and LRF/ZBTB7A expression levels. In vitro treatment of hematopoietic stem cells (HSCs) with HU induced a significant DNA hypomethylation pattern in ZBTB7A (p*, 0.04) and GATA2 (p*, 0.03) CpGs exclusively in the HU non-responders. Also, this group of patients exhibited significantly elevated baseline methylation patterns in ZBTB7A, before the HU treatment, compared to HU responders (p*, 0.019) and to control group of healthy individuals (p*, 0.021), which resembles a potential epigenetic barrier for the γ-globin expression. γ-Globin expression in vitro matched with detected HbF levels during patients’ monitoring tests (in vivo) under HU treatment, implying a good reproducibility of the in vitro HU epigenetic effect. LRF/ZBTB7A expression was elevated only in the HU non-responders under the influence of HU. Conclusions This is one of the very first pharmacoepigenomic studies indicating that the hypomethylation of ZBTB7A during HU treatment enhances the LRF expression, which by its turn suppresses the HbF resumption in the HU non-responders. Its role as an epigenetic regulator of hemoglobin switching is also supported by the wide distribution of ZBTB7A-binding sites within the 5′ CpG sequences of all studied human HBB cluster “modifier genes.” Also, the baseline methylation level of selective CpGs in ZBTB7A and GATA2 could be an indicator of the negative HU response among the β-type hemoglobinopathy patients

Б1.В.ОД.15.4 Этология и зоопсихология 2018 очная

Increased apoptotic activity in xenograft tumors (day 35) treated with miR-410 relative to miR-NC, assessed by caspase 3/7 ELISA assay (Promega). (PPTX 50.3 kb

Patient-reported outcomes from a randomized phase II study of the deferasirox film-coated tablet in patients with transfusion-dependent anemias

Abstract Background Adherence to long-term chelation therapy in transfusion-dependent patients is critical to prevent iron overload-related complications. Once-daily deferasirox dispersible tablets (DT) have proven long-term efficacy and safety in patients ≥2 years old with chronic transfusional iron overload. However, barriers to optimal adherence remain, including palatability, preparation time, and requirements for fasting state. A new film-coated tablet (FCT) formulation was developed, swallowed once daily (whole/crushed) with/without a light meal. Methods The open-label, Phase II ECLIPSE study evaluated patient-reported outcomes (PROs) in transfusion-dependent thalassemia or lower-risk myelodysplastic syndromes patients randomized 1:1 to receive deferasirox DT or FCT over 24 weeks as a secondary outcome of the study. Three PRO questionnaires were developed to evaluate both deferasirox formulations: 1) Modified Satisfaction with Iron Chelation Therapy Questionnaire; 2) Palatability Questionnaire; 3) Gastrointestinal (GI) Symptom Diary. Results One hundred seventy three patients were enrolled; 87 received the FCT and 86 the DT formulation. FCT recipients consistently reported better adherence (easier to take medication, less bothered by time to prepare medication and waiting time before eating), greater satisfaction/preference (general satisfaction and with administration of medicine), and fewer concerns (less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects). FCT recipients reported no taste or aftertaste and could swallow all their medicine with an acceptable amount of liquid. GI summary scores were low for both formulations. Conclusions These findings suggest a preference in favor of the deferasirox FCT formulation regardless of underlying disease or age group. Better patient satisfaction and adherence to chelation therapy may reduce iron overload-related complications. Trial registration ClinicalTrials.gov identifier: NCT02125877; registered April 26, 2014