Jorge Arbelbide

Hospital Italiano de Buenos Aires, Buenos Aires, Buenos Aires F.D., Argentina

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Publications (14)24.11 Total impact

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    ABSTRACT: The core complex of telomere-associated proteins, named the shelterin complex, plays a critical role in telomere protection and telomere length (TL) homeostasis. In this study, we have explored changes in the expression of telomere-associated genes POT1, TIN2, RAP1 and TPP1, in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). A total of 154 patients: 70 with MGUS and 84 with MM were studied. Real-time quantitative PCR was used to quantify gene expression. TL was evaluated by Terminal Restriction Fragments. Our data showed increased expression of POT1, TPP1, TIN2 and RAP1 in MM with respect to MGUS patients, with significant differences for POT1 gene (p=0.002). In MM, the correlation of gene expression profiles with clinical characteristics highlighted POT1 for its significant association with advanced clinical stages, high calcium and β2-microglobulin levels (p=0.02) and bone lesions (p=0.009). In multivariate analysis, POT1 expression (p=0.04) was a significant independent prognostic factor for overall survival as well as the staging system (ISS) (p<0.02). Our findings suggest for the first time the participation of POT1 in the transformation process from MGUS to MM, and provide evidence of this gene as a useful prognostic factor in MM as well as a possible molecular target to design new therapeutic strategies.
    Blood Cells Molecules and Diseases 11/2013; · 2.26 Impact Factor
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    Annals of Hematology 07/2013; · 2.87 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) include a group of heterogeneous hematological disorders with a variable risk of leukemic evolution and short survival. Around 40-50% of patients show abnormal karyotypes that are mostly characterized by monosomies or deletions. Cytogenetic findings are an independent prognostic factor and the International prognostic scoring system (IPSS) differentiates three cytogenetic categories, despite the Intermediate one being heterogeneous. The aim of this study, including 421 Argentinean patients with primary MDS, is to characterize the cytogenetic profile, to test its prognostic value and to compare partial and monosomal karyotypes against other cytogenetic findings. An abnormal karyotype (median survival: 26 months) was observed in 176 patients. The presence of complex karyotypes, number of alterations, and the IPSS cytogenetic groups showed significant differences for predicting outcome. Behavior of patients with isolated deletions (median survival: 49 months) did not differ from those with normal karyotype (56 months, P = 0.654) or Good prognostic findings (43 months, P = 0.371). However, a worse prognosis was observed when another alteration was added (31 months, P = 0.043). Karyotypes with autosomal monosomies (median survival: 16 months) had a prognostic impact similar to other Poor cytogenetic findings (17 months, P = 0.626). In our population classified according to French-American-British (FAB) or World Health Organization (WHO), this new categorization of cytogenetic abnormalities, recognizing three different risk groups, showed an independent prognostic impact and a better discriminating power than the IPSS categories. It can be concluded that all isolate deletions (excluding 7q-) are good prognostic findings and all monosomies (excluding Y chromosome loss) are bad indicators.
    American Journal of Hematology 07/2011; 86(7):540-5. · 4.00 Impact Factor
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    ABSTRACT: Chromosome abnormalities detected in metaphases from multiple myeloma (MM) cells have a clear impact on prognosis and response to therapy. Thirteen out of 50 (26%) patients with plasma cell disorders and abnormal karyotypes (11 with MM and 2 with plasma cell leukemia (PCL)) were selected for inclusion in the present report based on the presence of karyotypes with new and/or infrequent structural aberrations. Thirty-three new rearrangements, including a novel recurrent aberration: psu dic(5;1)(q35;q10), were detected. Chromosome 1 was the most frequently involved. Gains of genetic material (57%) were noted more frequently than losses (43%). Three rearrangements that were observed only once in the literature appear to be recurrent from our data: del(16)(q13), del(5)(p13) and i(3)(q10), the latter being a single structural aberration in the karyotype. Clinical parameters from our series were compared with 2 control groups: 20 MM cases with recurrent aberrations in MM/PCL with a similar distribution of abnormalities associated with poor prognosis (group 1), and 40 with normal karyotypes and fluorescence in situ hybridization analysis (group 2). Significantly increased serum calcium levels (p = 0.022) in patients with new and/or infrequent chromosome changes with respect to both control groups, and a higher percentage of bone marrow plasma cell infiltration (p = 0.005), β(2) microglobulin, and lactate dehydrogenase levels (p < 0.0001) compared to group 2 were observed. Our results suggest that some of these novel rearrangements may be capable to deregulate genetic mechanisms related to the development and/or progression of the disease. The finding of new recurrent aberrations supports this hypothesis.
    Cytogenetic and Genome Research 01/2011; 134(4):249-59. · 1.84 Impact Factor
  • Leukemia Research - LEUK RES. 01/2011; 35.
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    ABSTRACT: Iron overload (IO) is defined as an increase in storage iron, regardless of the presence or absence of tissue damage. Whether increased iron stores are involved in the pathogenesis of cardiovascular disease remains controversial.  To study insulin resistance markers, lipoprotein profile, activities of anti and prooxidant enzymes and cholesteryl ester transfer protein (CETP) in patients with IO. Twenty male patients with IO were compared with 20 sex- and age-matched controls. General biochemical parameters, lipoprotein profile, and activities of paraoxonase 1, employing two substrates, paraoxon (PON) and phenylacetate (ARE), lipoprotein-associated phospholipase A(2) (Lp-PLA(2) ) and CETP were determined. IO patients showed higher levels of HOMA-IR and triglycerides [median (Q1-Q3)] [128 (93-193) vs. 79(51-91) mg dL(-1) , P < 0·0005] while lower high-density lipoprotein (HDL) cholesterol (mean ± SD) (41 ± 9 vs. 52 ± 10 mg dL(-1) , P < 0·0005) in comparison with controls. Moreover, the triglycerides/HDL-cholesterol [3·2 (2·0-5·1) vs. 1·5 (1·0-1·9), P < 0·0005] ratio and oxidized low-density lipoprotein levels [94 (64-103) vs. 68 (59-70) IU L(-1) , P < 0·05] were increased in the patient group. Although no difference was observed in ARE activity, PON activity was decreased in IO patients [246 (127-410) vs. 428 (263-516) nmol mL(-1) min(-1) , P < 0·05]. In addition, CETP and Lp-PLA(2) activities were also increased in the patients (189 ± 31 vs. 155 ± 36% ml(-1)  h(-1) , P < 0·005; and 10·1 ± 2·9 vs. 8·2 ± 2·4 μmol mL(-1) h(-1) , P < 0·05, respectively). Associations between ferritin concentration and the alterations in lipid metabolism were also found. Multiple regression analyses identified HOMA-IR as independent predictor of CETP activity (B = 65·9, P < 0·0001, r(2) = 0·35), as well as ferritin concentration of Lp-PLA(2) activity (B = 3·7, P < 0·0001, r(2) = 0·40) after adjusting for confounding variables.   IO patients presented not only insulin resistance but also metabolic alterations that were related to elevated iron stores and are associated with high risk of cardiovascular disease.
    European Journal of Clinical Investigation 12/2010; 41(5):479-86. · 3.37 Impact Factor
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    ABSTRACT: In this study, we explored changes in the expression of the telomere maintenance genes, TRF1, TRF2 and TANK1 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Results were correlated with human telomerase reverse transcriptase (hTERT ) expression, telomere length (TL) and clinicopathological characteristics. Bone marrow (BM) samples from 132 patients, 64 with MGUS and 68 with MM, were studied. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify gene expression. TL was evaluated by terminal restriction fragment length analysis. MGUS patients showed increased TRF1 levels (P = 0.006) and lower expression of TRF2 (P = 0.005) and TANK1 (P = 0.003) compared with MM patients. For hTERT analysis, patients were divided into three groups by use of receiver operating characteristics: low (group I [GI]), intermediate (group II [GII]) and high (group III [GIII]) expression. We observed increasing expression of TRF2 and TANK1 from GI to GIII in MGUS and MM, with differences for both genes in MM (P < 0.01) and for TRF2 in MGUS (P < 0.01). GIII patients with the highest telomerase expression had the shortest TL. In both entities, a positive association between TRF2-TANK1, TRF2-hTERT and TANK1-hTERT (P ≤ 0.01) was observed. In MM, the percentage of BM infiltration and Ki-67 index were positively associated with TRF2, TANK1 and hTERT expression (P ≤ 0.03) and negatively with TL (P = 0.02), whereas lactate dehydrogenase was significantly correlated with TRF2 mRNA (P = 0.008). Our findings provide the first evidence of a modification in the expression of telomeric proteins in plasma cell disorders, and suggest that mechanisms other than telomerase activation are involved in TL maintenance in these pathologies.
    Molecular Medicine 01/2010; 16(11-12):471-8. · 4.47 Impact Factor
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    ABSTRACT: To characterize the lipid-related atherogenic risk factors in iron deficiency anaemia (IDA) patients. Twenty IDA women were compared to healthy age-matched controls. Lipoprotein profile, cholesteryl ester transfer protein (CETP), paraoxonase (PON) 1 and lipoprotein-associated phospholipase A(2) (LpPLA(2)) activities and plasma levels of oxidized-LDL were evaluated. Triglycerides were higher (median [range]) (1.0 [0.5-1.9] vs. 0.7 [0.5-1.5] mmol/L, p<0.05) and HDL-C lower (mean + or - SD) (1.3 + or - 0.3 vs. 1.6 + or - 0.4 mmol/L, p<0.01) in the patients group. CETP (197 + or - 29% vs. 151 + or - 29% mL(-1) h(-1), p<0.001), PON 1 (122 + or - 17 vs. 140 + or - 33 micromol mL(-1) min(-1), p<0.05) and LpPLA(2) (9.6 + or - 2.0 vs. 8.1 + or - 1.7 micromol mL(-1) h(-1), p<0.05) activities were different in IDA women. No difference was observed in oxidized-LDL. Haemoglobin correlated negatively with triglycerides (r=-0.35, p<0.05), CETP (r=-0.62, p<0.001) and LpPLA(2) (r=-0.34, p<0.05), while ferritin was positively associated with HDL-C (r=0.39, p<0.05) and inversely with CETP (r=-0.49, p<0.005). The alterations in lipoprotein profile, CETP, PON 1 and LpPLA(2) activities described in the present study indicate that non-treated IDA might represent a proatherogenic state.
    Clinical biochemistry 10/2009; 43(4-5):416-23. · 2.02 Impact Factor
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    ABSTRACT: Aberrant DNA methylation is considered an important epigenetic mechanism for gene inactivation. Monoclonal gammopathy of undetermined significance (MGUS) is believed to be a precursor of multiple myeloma (MM). We have analyzed methylation status of p15 INK4B , p16 INK4A , ARF, SOCS-1, p27 KIP1 , RASSF1A, and TP73 genes in bone marrow DNA samples from 21 MGUS and 44 MM patients, in order to determine the role of aberrant promoter methylation as one of the steps involved in the progression of MGUS to MM. Methylation specific polymerase chain reaction assay followed by DNA sequencing of the resulting product was performed. SOCS-1 gene methylation was significantly more frequent in MM (52%) than in MGUS (14%; p=0,006). Methylation frequencies of TP73, ARF, p15 INK4B , p16 INK4A , and RASSF1A were comparable in MGUS: 33%, 29%, 29%, 5%, and 0%, to that observed in MM: 45%, 29%, 32%, 7%, and 2%. All patients lacked methylation at p27 KIP1 gene. In both entities, a concurrent methylation of p15 INK4B and TP73 was observed. The mean methylation index of MGUS was lower (0.16) than that of MM (0.24; p<0.05). Correlations with clinicopathologic characteristics showed a higher mean age in MGUS patients with SOCS-1 methylated (p<0.001); meanwhile in MM, methylation of p15 INK4B was more frequent in males (p=0.009) and IgG isotype (p=0.038). Our findings suggest methylation of TP73, ARF, p15 INK4B , and p16 INK4A as early events in the pathogenesis and development of plasma cell disorders; meanwhile, SOCS-1 methylation would be an important step in the clonal evolution from MGUS to MM.
    Annals of Hematology 09/2009; 89(2):191-9. · 2.87 Impact Factor
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    ABSTRACT: La amiloidosis es una enfermedad infiltrativa sistémica que compromete al corazón y representa una causa importante de miocardiopatía restrictiva. Se describe el caso de un paciente masculino de 35 años con insuficiencia cardíaca avanzada secundaria a miocardiopatía infiltrativa por depósito amiloide. Durante su evaluación se realizó diagnóstico de neoplasia de células plasmáticas. Debido a la rápida progresión de los síntomas, el deterioro de la función ventricular y la incapacidad para tolerar el tratamiento adecuado para su enfermedad hematológica, se realizó trasplante cardíaco seguido de trasplante autólogo de médula ósea sin complicaciones. La presentación de este caso constituye la primera comunicación en nuestro país de trasplante cardíaco seguido de trasplante de médula ósea como tratamiento de la amiloidosis cardíaca.
    Revista argentina de cardiología. 08/2009; 77(4):309-311.
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    ABSTRACT: Introduction, Iron overload (IO) is characterized by a sustained increase in iron stores, which could generate highly oxidative species via Haber-Weiss reaction. Objectives, To study the lipoprotein profi le, the activity of anti and prooxidant enzymes and other lipoprotein-associated proteins in patients with IO. Design and Methods, Fifteen patients with IO were compared with 15 sex and age-matched healthy controls. General biochemical parameters, the lipoprotein profi le, and the activities of paraoxonase 1, evaluated employing two substrates, paraoxon (PON) and phenylacetate (ARE), lipoprotein associated phospholipase A2 (Lp-PLA2) and cholesteryl ester transfer protein (CETP) were determined. Results, IO patients showed higher levels of triglycerides (TG) (median [interquartile range]) (132 [96-193] vs. 71 [47-91] mg/dl, p
    Bioquímica y Patología Clínica. 01/2009; 73(2):39-46.
  • Leukemia Research - LEUK RES. 01/2009; 33.
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    ABSTRACT: An important number of patients with Acute Myeloid Leukemia (AML) experience relapse or resistance to chemotherapy. One of the mechanisms involved in this resistance is the presence of glycoprotein P170 (gp-P 170), which results of the MDR-1 gene in leukemic cells. The objective of this article is to assess the prognostic impact of the expression of MDR-1 in a group of patients treated for AML. The expression of MDR-1 was retrospectively assessed in a cohort of 55 patients with AML, older than 16 years old, who received chemotherapy from 1990 to 2000. The presence of MDR-1/gp-P170 was evaluated on bone marrow biopsy by immunohisto-chemistry. A ROC curve established that an expression of > 50% of MDR-1 on blastic cells was significant for the achievement of complete remission. The expression of MDR-1+ correlated with the presence of leucocytosis (p:0.002), expression of CD34+ cells (p:0.006), less achievement of complete remission (p:0.001), more rate of relapse (p:0.02) and of non-favorable cytogenetics (p:0.02). The event-free survival was of 21.2% SE:9.3 with a follow up of 22 months for the group of MDR-1+ versus 56.4% SE 12.5 with a follow-up of 78 months for the MDR-1-group (p:0.007). It can be concluded that the expression of MDR-1 is a prognostic factor of resistance to chemotherapy. These patients present a lower rate of complete remission, a higher rate of relapse with persistence of post treatment residual disease, which produces a shorter global survival.
    Medicina 01/2003; 63(4):277-82. · 0.42 Impact Factor
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    ABSTRACT: Prognostic value of the expression of MDR-1 in acute myeloid leukemia. An important number of patients with Acute Myeloid Leukemia (AML) experience relapse or resistance to chemotherapy. One of the mechanisms involved in this resistance is the presence of glycoprotein P170 (gp-P 170), which results of the MDR-1 gene in leukemic cells. The objective of this article is to assess the prognostic impact of the expression of MDR-1 in a group of patients treated for AML. The expression of MDR-1 was retrospectively assessed in a cohort of 55 patients with AML, older than 16 years old, who received chemotherapy from 1990 to 2000. The presence of MDR-1/gp-P170 was evaluated on bone marrow biopsy by immunohisto-chemistry. A ROC curve established that an expression of > 50% of MDR-1 on blastic cells was significant for the achievement of complete remission. The expression of MDR-1+ correlated with the presence of leucocytosis (p:0.002), expression of CD34+ cells (p:0.006), less achievement of complete remission (p:0.001), more rate of relapse (p:0.02) and of non-favorable cytogenetics (p:0.02). The event-free survival was of 21.2% SE:9.3 with a follow up of 22 months for the group of MDR-1+ versus 56.4% SE 12.5 with a follow-up of 78 months for the MDR-1- group (p:0.007). It can be concluded that the expression of MDR-1 is a prognostic factor of resistance to chemotherapy. These patients present a lower rate of complete remission, a higher rate of relapse with persistence of post treatment residual disease, which produces a shorter global survival.

Publication Stats

39 Citations
24.11 Total Impact Points

Institutions

  • 2003–2013
    • Hospital Italiano de Buenos Aires
      • • Department of Pediatric Hematology
      • • Department of Pathological Anatomy
      Buenos Aires, Buenos Aires F.D., Argentina
  • 2009–2010
    • Academia Nacional de Medicina
      Buenos Aires, Buenos Aires F.D., Argentina