13 research outputs found
In vitro apoptotic effects of farnesyltransferase blockade in acute myeloid leukemia cells
Farnesyltransferase inhibitors (FTIs)
are a class of oral anti-cancer drugs currently tested
in phase I-II clinical trials for treatment of
hematological malignancies. The in vitro effects of
various FTIs (alpha-hydroxyfarnesylphosphonic
acid, manumycin-A and SCH66336) were tested on
CD34+ KG1a cell line and in primary acute myeloid
leukemia (AML) cells from 64 patients. By cell
viability and clonogeneic methylcellulose assays,
FTIs showed a significant inhibitory activity in
CD34+ KG1a and primary bone marrow (BM)
leukemic cells from 56% of AML patients. FTIs also
induced activation of caspase-3 and Fas-independent
apoptosis, confirmed by the finding that inhibition of
caspase-8 was not associated with the rescue of FTItreated cells. We concluded that other cellular events
induced by FTIs may trigger activation of caspase-3
and subsequent apoptosis, but the expression of
proapoptotic molecules, as Bcl-2 and Bcl-XL, and
antiapoptotic, as Bcl-X(s), were not modified by
FTIs. By contrast, expression of inducible nitric
oxide synthase (iNOS) was increased in FTI-treated
AML cells. Our results suggest a very complex
mechanism of action of FTIs that require more
studies for a better clinical use of the drugs alone or
in combination in the treatment of hematological
malignancies
Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?
BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10Â years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin
Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?
Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and
Efficacy and safety of splenectomy in adult autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) is a rare hematologic disease, primarily affecting adults or children with immunodeficiency disease. First-line therapy consists of long course of steroids administration, with an early complete response rate (CRr) of 75-80%, but up to 20-30% of patients requires a second-line therapy. Rituximab is the first choice in refractory old AIHA patients, because of its safety and efficacy (early CRr at 80-90% and at 68% at 2-3 years). For this reason, splenectomy is even less chosen as second-line therapy in elderly, even though laparoscopic technique decreased complication and mortality rates. However, splenectomy can be still considered a good therapeutic option with a CRr of 81% at 35.6 months in patients older than 60 year-old, when rituximab administration cannot be performed
Hemoglobin normalization after splenectomy in a paroxysmal nocturnal hemoglobinuria patient treated by eculizumab
Oxidative stress in chronic lymphocytic leukemia: still a matter of debate
There is a large body of evidence showing a strong correlation between carcinogenesis of several types of human tumors, including chronic lymphocytic leukemia (CLL), and oxidative stress (OS). The mechanisms by which OS may promote cancer pathogenesis have not been completely deciphered yet and, in CLL, as in other neoplasms, whether OS is a primary cause or simply a downstream effect of the disease is still an open question. It has been demonstrated that, in CLL, OS concomitantly results from increased reactive oxygen species (ROS) production, mainly ascribable to CLL cells mitochondrial activity, and impaired antioxidant defenses. Interestingly, OS evaluation in CLL patients, at diagnosis, seems to have a prognostic significance, thus getting new insights in the biological comprehension of the disease with potential therapeutic implications
CD200 and Chronic Lymphocytic Leukemia: Biological and Clinical Relevance
CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin protein
superfamily, is broadly expressed on a wide variety of cell types, such as B lymphocytes, a
subset of T lymphocytes, dendritic cells, endothelial and neuronal cells. It delivers
immunosuppressive signals through its receptor CD200R, which is expressed on
monocytes/myeloid cells and T lymphocytes. Moreover, interaction of CD200 with
CD200R has also been reported to play a role in the regulation of tumor immunity.
Overexpression of CD200 has been reported in chronic lymphocytic leukemia (CLL) and
hairy cell leukemia but not in mantle cell lymphoma, thus helping to better discriminate
between these different B cell malignancies with different prognosis. In this review, we focus
on the role of CD200 expression in the differential diagnosis of mature B-cell neoplasms and
on the prognostic significance of CD200 expression in CLL, where conflicting results have
been published so far. Of interest, increasing evidences indicate that anti-CD200 treatment
might be therapeutically beneficial for treating CD200-expressing malignancies, such as CLL