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Maria Antonietta Aloe Spiriti - One of the best experts on this subject based on the ideXlab platform.

  • changes in rps14 expression levels during lenalidomide treatment in low and intermediate 1 risk myelodysplastic syndromes with Chromosome 5q deletion
    European Journal of Haematology, 2010
    Co-Authors: Esther Oliva, Maria Cuzzola, Francesco Nobile, Francesca Ronco, Carmelo Laganà, Fortunato Morabito, Sara Galimberti, Agostino Cortelezzi, Maria Grazia Derrigo, Maria Antonietta Aloe Spiriti
    Abstract:

    Background:  Haploinsufficiency of the ribosomal protein S14 RPS14 gene, located in the common deleted region of Chromosome 5q, is a potential causal factor of 5q− syndrome. Lenalidomide elicits high response rates and morphological improvements in myelodysplastic syndrome (MDS) patients with Chromosome 5q deletion [del(5q)]. Methods:  To further evaluate the role of RPS14, its transcription was tested in bone marrow cells from 17 patients with International Prognostic Scoring System defined Low- or Intermediate-1-risk MDS with del(5q) as a single or additional cytogenetic abnormality receiving treatment with lenalidomide. Results:  After 12 wk of lenalidomide treatment, erythroid responses were observed in all cases with an increase in hemoglobin levels of 2.7 ± 2.5 g/dL (up to a mean 11.8 ± 1.9 g/dL; P = 0.001). Before treatment, RPS14 expression levels were under-expressed in 15 patients with respect to normal controls. After 12 wk of lenalidomide treatment, all patients had an erythroid response. There was a significant increase in median RPS14 expression from baseline 0.01 (IQR 0.05–0.31) to 12 wk 204.71-fold (2.86–446.32; P < 0.0001). Conclusions:  These observations in the patient setting support the importance of RPS14 in the pathogenesis of MDS with del(5q).

  • Changes in RPS14 expression levels during lenalidomide treatment in Low- and Intermediate-1-risk myelodysplastic syndromes with Chromosome 5q deletion.
    European journal of haematology, 2010
    Co-Authors: Esther Oliva, Maria Cuzzola, Francesco Nobile, Francesca Ronco, Maria Grazia D'errigo, Carmelo Laganà, Fortunato Morabito, Sara Galimberti, Agostino Cortelezzi, Maria Antonietta Aloe Spiriti
    Abstract:

    Background:  Haploinsufficiency of the ribosomal protein S14 RPS14 gene, located in the common deleted region of Chromosome 5q, is a potential causal factor of 5q− syndrome. Lenalidomide elicits high response rates and morphological improvements in myelodysplastic syndrome (MDS) patients with Chromosome 5q deletion [del(5q)]. Methods:  To further evaluate the role of RPS14, its transcription was tested in bone marrow cells from 17 patients with International Prognostic Scoring System defined Low- or Intermediate-1-risk MDS with del(5q) as a single or additional cytogenetic abnormality receiving treatment with lenalidomide. Results:  After 12 wk of lenalidomide treatment, erythroid responses were observed in all cases with an increase in hemoglobin levels of 2.7 ± 2.5 g/dL (up to a mean 11.8 ± 1.9 g/dL; P = 0.001). Before treatment, RPS14 expression levels were under-expressed in 15 patients with respect to normal controls. After 12 wk of lenalidomide treatment, all patients had an erythroid response. There was a significant increase in median RPS14 expression from baseline 0.01 (IQR 0.05–0.31) to 12 wk 204.71-fold (2.86–446.32; P 

Alan F. List - One of the best experts on this subject based on the ideXlab platform.

  • Deletion 5q MDS: Molecular and therapeutic implications
    Best practice & research. Clinical haematology, 2013
    Co-Authors: Rami S. Komrokji, Benjamin L. Ebert, Eric Padron, Alan F. List
    Abstract:

    Heterozygous, interstitial deletions of Chromosome 5q are the most common cytogenetic abnormality in myelodysplastic syndromes (MDS). This chromosomal abnormality is associated with a consistent clinical phenotype, the 5q- syndrome, in a subset of patients, and therapeutic sensitivity to the drug lenalidomide. No genes on Chromosome 5q undergo recurrent homozygous inactivation in MDS patients. Instead, haploinsufficiency for key genes powerfully alters hematopoiesis, leading to the MDS phenotype in patients with del(5q). Haploinsufficiency for the RPS14 gene leads to activation of the p53 pathway and the macrocytic anemia characteristic of this disorder, and loss of p53 rescues erythropoiesis and facilitates clonal progression. Other genes, as well as miR-145 and miR-146a, contribute to aberrant megakaryopoiesis and a selective advantage for the del(5q) clone. The integrated effects of haploinsufficiency for these key genes, in aggregate, lead to the full phenotype of the disorder.

  • The role of lenalidomide in the treatment of patients with Chromosome 5q deletion and other myelodysplastic syndromes.
    Current opinion in hematology, 2007
    Co-Authors: Magda Melchert, Vishakha Kale, Alan F. List
    Abstract:

    PURPOSE OF REVIEW The aim of this article is to discuss the relevant pathobiologic effects of lenalidomide and the most recent clinical evidence to support its use in patients with myelodysplastic syndrome. RECENT FINDINGS Lenalidomide is an immunomodulatory agent with biological activity in several hematologic malignancies, including myelodysplastic syndrome. The precise mechanism yielding benefit in patients with myelodysplastic syndrome and 5q- syndrome is not clear, but various molecular and pathogenic targets have been identified. Enhancement of cellular immunity through T-cell and NK-cell activation and suppression of inflammatory cytokines and pro-angiogenic peptides upon lenalidomide treatment has been demonstrated in in-vitro models of myelodysplastic syndrome. Furthermore, lenalidomide induces a direct cytotoxic effect against 5q- clones in leukemia cell lines and enhances ligand-induced erythropoietin receptor signaling in erythroid progenitors. Clinical trials with lenalidomide in myelodysplastic syndrome have supported the in-vitro evidence of karyotype-dependent activity by demonstration of a high frequency of cytogenetic and pathologic responses in patients with myelodysplastic syndrome and deletion of Chromosome 5q. Lenalidomide was approved for the treatment of transfusion-dependent patients with low to intermediate risk myelodysplastic syndrome and Chromosome 5q deletion. SUMMARY Lenalidomide is an active immunomodulatory agent for the treatment of myelodysplastic syndrome with encouraging erythropoetic and cytogenetic remitting activity that is karyotype dependent.

  • lenalidomide in the myelodysplastic syndrome with Chromosome 5q deletion
    The New England Journal of Medicine, 2006
    Co-Authors: Alan F. List, Gordon W. Dewald, John M Bennett, Aristotle Giagounidis, Azra Raza, Eric J Feldman, Bayard L Powell, Peter L Greenberg, Deborah A Thomas, Richard Stone
    Abstract:

    Background Severe, often refractory anemia is characteristic of the myelodysplastic syndrome associated with Chromosome 5q31 deletion. We investigated whether lenalidomide (CC5013) could reduce the transfusion requirement and suppress the abnormal 5q31− clone in patients with this disorder. Methods One hundred forty-eight patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily. Hematologic, bone marrow, and cytogenetic changes were assessed after 24 weeks of treatment by an intention-to-treat analysis. Results Among the 148 patients, 112 had a reduced need for transfusions (76%; 95% confidence interval [CI], 68 to 82) and 99 patients (67%; 95% CI, 59 to 74) no longer required transfusions, regardless of the karyotype complexity. The response to lenalidomide was rapid (median time to response, 4.6 weeks; range, 1 to 49) and sustained; the median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. The maximum hemoglobin concentration reached...

Esther Oliva - One of the best experts on this subject based on the ideXlab platform.

  • changes in rps14 expression levels during lenalidomide treatment in low and intermediate 1 risk myelodysplastic syndromes with Chromosome 5q deletion
    European Journal of Haematology, 2010
    Co-Authors: Esther Oliva, Maria Cuzzola, Francesco Nobile, Francesca Ronco, Carmelo Laganà, Fortunato Morabito, Sara Galimberti, Agostino Cortelezzi, Maria Grazia Derrigo, Maria Antonietta Aloe Spiriti
    Abstract:

    Background:  Haploinsufficiency of the ribosomal protein S14 RPS14 gene, located in the common deleted region of Chromosome 5q, is a potential causal factor of 5q− syndrome. Lenalidomide elicits high response rates and morphological improvements in myelodysplastic syndrome (MDS) patients with Chromosome 5q deletion [del(5q)]. Methods:  To further evaluate the role of RPS14, its transcription was tested in bone marrow cells from 17 patients with International Prognostic Scoring System defined Low- or Intermediate-1-risk MDS with del(5q) as a single or additional cytogenetic abnormality receiving treatment with lenalidomide. Results:  After 12 wk of lenalidomide treatment, erythroid responses were observed in all cases with an increase in hemoglobin levels of 2.7 ± 2.5 g/dL (up to a mean 11.8 ± 1.9 g/dL; P = 0.001). Before treatment, RPS14 expression levels were under-expressed in 15 patients with respect to normal controls. After 12 wk of lenalidomide treatment, all patients had an erythroid response. There was a significant increase in median RPS14 expression from baseline 0.01 (IQR 0.05–0.31) to 12 wk 204.71-fold (2.86–446.32; P < 0.0001). Conclusions:  These observations in the patient setting support the importance of RPS14 in the pathogenesis of MDS with del(5q).

  • Changes in RPS14 expression levels during lenalidomide treatment in Low- and Intermediate-1-risk myelodysplastic syndromes with Chromosome 5q deletion.
    European journal of haematology, 2010
    Co-Authors: Esther Oliva, Maria Cuzzola, Francesco Nobile, Francesca Ronco, Maria Grazia D'errigo, Carmelo Laganà, Fortunato Morabito, Sara Galimberti, Agostino Cortelezzi, Maria Antonietta Aloe Spiriti
    Abstract:

    Background:  Haploinsufficiency of the ribosomal protein S14 RPS14 gene, located in the common deleted region of Chromosome 5q, is a potential causal factor of 5q− syndrome. Lenalidomide elicits high response rates and morphological improvements in myelodysplastic syndrome (MDS) patients with Chromosome 5q deletion [del(5q)]. Methods:  To further evaluate the role of RPS14, its transcription was tested in bone marrow cells from 17 patients with International Prognostic Scoring System defined Low- or Intermediate-1-risk MDS with del(5q) as a single or additional cytogenetic abnormality receiving treatment with lenalidomide. Results:  After 12 wk of lenalidomide treatment, erythroid responses were observed in all cases with an increase in hemoglobin levels of 2.7 ± 2.5 g/dL (up to a mean 11.8 ± 1.9 g/dL; P = 0.001). Before treatment, RPS14 expression levels were under-expressed in 15 patients with respect to normal controls. After 12 wk of lenalidomide treatment, all patients had an erythroid response. There was a significant increase in median RPS14 expression from baseline 0.01 (IQR 0.05–0.31) to 12 wk 204.71-fold (2.86–446.32; P 

Brian Shuch - One of the best experts on this subject based on the ideXlab platform.

Sabine Rudnikschoneborn - One of the best experts on this subject based on the ideXlab platform.

  • 93rd enmc international workshop non 5q spinal muscular atrophies sma clinical picture 6 8 april 2001 naarden the netherlands
    Neuromuscular Disorders, 2003
    Co-Authors: Klaus Zerres, Sabine Rudnikschoneborn
    Abstract:

    This 93rd SMA workshop followed the European Neuromuscular Centre (ENMC) tradition to combine clinical and molecular topics with the aim of not only exchanging current knowledge but also initiating collaborative studies. Despite important milestones in research on autosomal recessive SMA with localisation on Chromosome 5q (SMA 5q) in the past 10 years, we are just beginning to understand the molecular basis and phenotypic spectrum of non-5q-SMA entities. The possibility of analysing the SMN gene allowed the delineation of the diagnostic criteria of ‘classical’ proximal SMA and its clinical variability. On the other hand, different entities of SMA could be defined that show atypical features and proved to be unlinked to Chromosome 5q. The field of interest has therefore been focussed on further genes responsible for anterior horn cell loss. This will contribute to further understand the underlying pathogenetic pathways, the complex protein interactions and genotype–phenotype correlations in various types of motor neuron disorders. The workshop was structured in a first part, briefly reviewing the current status of SMA 5q including animal models which have been generated. The second part included different sessions on non-5q-SMA forms; clinical and diagnostic criteria were discussed and adapted to current knowledge. These were summarized by invited chairpersons (named in brackets) and followed by contributions of the participants. The following short summaries cover the essentials of the reviews, the discussion and the consensus achieved. 1. Update on SMA 5q

  • exclusion of the gene locus for spinal muscular atrophy on Chromosome 5q in a family with infantile olivopontocerebellar atrophy opca and anterior horn cell degeneration
    Neuromuscular Disorders, 1995
    Co-Authors: Sabine Rudnikschoneborn, Brunhilde Wirth, Dorothee Rohrig, Helmut Saule, Klaus Zerres
    Abstract:

    Abstract Two sisters with infantile OPCA plus spinal muscular atrophy (SMA) are reported. Both showed severe hypotonia and psychomotor delay from birth, and in addition, nystag moid eye movements and vision impairment were evident. Cerebellar hypoplasia with cystic dilatation was seen by neuro-imaging methods. Pathoanatomically, a marked cerebellar hypoplasia and neuronal loss in the basal ganglia, brainstem and anterior horns were found in the deceased girl. Linkage studies with polymorphic markers of the region 5q11.2-q13.3 flanking the gene locus for infantile SMA showed identical parental haplotypes in the patients and their older healthy sister. It can be concluded that the gene locus for infantile SMA on Chromosome 5q is not responsible for infantile OPCA plus anterior horn cell degeneration in the described family which might apply to this disorder in general.