NKG2D ligands (NKG2DL) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. Various immune cells express ...NKG2D receptors, including natural killer (NK) cells and CD8
T cells. Interactions between NKG2DL and NKG2D receptors are essential for NK-cell elimination of osteosarcoma tumor-initiating cells. In this report, we used NKG2D-NKG2DL interactions to optimize an immunotherapeutic strategy against osteosarcoma. We evaluated
and
the safety and cytotoxic capacity against osteosarcoma cells of CD45RA
memory T cells expressing an NKG2D-4-1BB-CD3z chimeric antigen receptor (CAR).
CD45RA
cells from healthy donors were transduced with NKG2D CARs containing 4-1BB and CD3z signaling domains. NKG2D CAR expression was analyzed by flow cytometry.
cytotoxicity of NKG2D-CAR
CD45RA
T cells against osteosarcoma was evaluated by performing conventional 4-hour europium-TDA release assays. For the
orthotopic model, 531MII YFP-luc osteosarcoma cells were used as targets in NOD-scid IL2Rg
mice.
Lentiviral transduction of NKG2D-4-1BB-CD3z markedly increased NKG2D surface expression in CD45RA
cells. Genetic stability was preserved in transduced cells.
, NKG2D-CAR
memory T cells showed significantly increased cytolytic activity than untransduced cells against osteosarcoma cell lines, while preserving the integrity of healthy cells. NKG2D-CAR
memory T cells had considerable antitumor activity in a mouse model of osteosarcoma, whereas untransduced T cells were ineffective.
Our results demonstrate NKG2D-4-1BB-CD3z CAR-redirected memory T cells target NKG2DL-expressing osteosarcoma cells
and
and could be a promising immunotherapeutic approach for patients with osteosarcoma.
.
Objective
Prenatal diagnoses of microdeletion syndromes without ultrasound findings in the first and second trimester are always difficult. The objective of this study is to report the prenatal ...ultrasound findings in four foetuses diagnosed with 17q21.31 microdeletions (Koolen‐de Vries syndrome) using chromosomal microarrays (CMA).
Patients and Methods
We present four foetuses with 17q21.31 microdeletion. All showed CNS anomalies in the third trimester, three had ventriculomegaly, and one hypogenesis of corpus callosum at 31 weeks of pregnancy.
Results
Array‐SNPs and CGH‐array were performed on uncultured amniocytes and peripheral blood revealing a 17q21.31 microdeletion.
Conclusions
Prenatal CNS anomalies (mainly ventriculomegaly) at third trimester, in spite of isolate, should be considered a prenatal ultrasound marker of this syndrome. This kind of malformations raise the possibility of an underlying genetic conditions including 17q21.31 microdeletion; thus, CMA should be taken into consideration when offering prenatal genetic counselling.
Prenatal CNS anomalies (mainly ventriculomegaly) at third trimester, should be considered a prenatal ultrasound marker of this syndrome. This kind of malformations raise the possibility of an underlying genetic condition including 17q21.31 microdeletion. Thus CMA should be taken into consideration when offering prenatal genetic counselling.
celiac disease is associated with the HLA class II alleles: DQA1*05-DQB1*02 and DQB1*0302. The genetic risk for celiac disease may depend on the presence or absence of such alleles, their combination ...or number of copies. This study aimed to establish the differences in HLA genotypes between celiac patients diagnosed during childhood and adulthood, and between patients and healthy controls, and to determine the risk of disease in each genotypic category.
we classified 350 celiac patients at time of diagnosis and 218 controls into 14 categories according to their HLA genotype, based on the presence or absence of risk alleles.
we found statistically significant differences between the genotype frequencies of celiac patients diagnosed as being children and adults. DQA1*05 (x 1 copy), DQB1*02 (x 1 copy), DQB1*0302 (x 0 copies) was the most frequent genotype in individuals diagnosed in childhood, whereas DQA1*05 (x 1 copy), DQB1*02 (x 2 copies), DQB1*0302 (x 0 copies) was the most frequent in adults. The risk for disease in each genotypic category in celiac children and adults turned out to be different. The presence of DQB1*0302 did not increase risk in children, but did in adults.
in our celiac population, we found a different genetic pattern according to age of diagnosis. That could suggest that the pathogenic mechanism of the disease is not exactly the same in both age groups, which could somehow determine clinical presentation of the disease, its epidemiology, coexisting diseases, and complications.
Abstract Chromosomal abnormalities are detected in 40–60% of patients with de novo myelodysplastic syndromes (MDS). This study used the FISH technique in 773 patients with de novo MDS without ...evidence of monosomy 7 (−7) or 7q deletion (7q−) by conventional G-banding cytogenetics (CC) to analyze their prognostic impact by FISH alone. FISH detected −7/7q− in 5.2% of patients. Presence of −7/7q− was associated with shorter overall survival than absence of such aberrations. Our results suggest that FISH 7q could be beneficial in patients with intermediate WHO morphologic risk stratification and no evidence of −7/7q− by CC.
We exposed human peripheral lymphocytes in vitro to 0.3 and 1 Gy of60Co gamma rays to evaluate whether the ability and sensitivity to detect chromosomal aberrations by chromosome painting is ...independent or not to the specific paint probes. To detect structural aberrations (translocations), we painted chromosome spreads simultaneously with two whole-chromosome libraries for chromosomes 1, 2, 3, 4, 5, 6, 7, 11, 13, 16, and 18. To compare the rate of chromosome translocations detected by the different pairs of chromosomes, data were normalized according to the fraction of genome painted and evaluated by unconditional logistic regression. Our results show that any combination of paint probes can be used to score induced chromosomal aberrations. We observed that the amounts of translocations are dose dependent and quite homogeneous within each dose of radiation, independently of chromosomes painted. However, the use of small chromosome probes is not recommended because of the high number of cells to be analyzed due to the small amount of genome painted and because it is more difficult to detect translocations in small chromosomes.
Hereditary hemochromatosis (HH) displays an important phenotypic variability and is a disease influenced by many factors.
We included 88 patients with HH. Main clinical and laboratory data were ...analyzed, and the influence of 6 variables on intensity of iron overload was evaluated.
In 38.6% (95% confidence interval CI, 28.5-49.6%) patients, none of the typical symptoms of the disease was observed. 30,9% (95% CI, 21.7-41.7%) showed abnormalities of the glucose metabolism. We detected an increase in sideremia in 75.0% patients (CI 95%, 64.4-83.3%), transferrin saturation index (TSI) in 95.4% (CI 95%, 88.1-98.5%) and ferritin in 93.2% (CI 95%, 85.1-97.1%) of patients. In addition, we observed increased values of GPT and alkaline phosphatase in an appreciable percentage of patients. Ferritin was significantly higher in men (1329.4 913.2 ng/ml vs 656.6 644.5 ng/ml; p < 0.001), and in those older than 45 years (1293.9 1006.9 ng/ml vs 868.9 642.8 ng/ml; p = 0.023 and in not blood donors (1205.2 926.8 vs 524.8 365.9 ng/ml; p < 0.001). TSI was 81.9% (19.6) in C282Y homozygotes and 65.7% (19.2) in the rest of HFE genotypes (p = 0.002). Differences of TSI with regard to sex, age or status of blood donor were not detected. Sideremia was significantly higher in patients infected by virus C (251.8 24.4 microg/dl vs 182.8 45.8 microg/dl; p = 0.001).
HH patients have a noticeable phenotypic variability, and for that reason clinical symptoms are only orientative for the diagnosis. The relationship between HH and glucose metabolism should be investigated further. Iron parameters can be influenced by age, sex, HFE genotype, blood donation, alcohol intake and hepatitis C virus infection.
In two patients with hematological neoplasias a tandem repetition of chromosome 21 in the bone marrow was revealed by cytogenetic analysis. The disease was different in the two patients: one was of ...the lymphoid type, acute lymphoblastic leukemia type L1, and the other was of the myeloid type, acute nonlymphoblastic leukemia type M2. In one case this chromosomal abnormality resulted in amplification of the
AML1 gene (HUGO nomenclature:
RUNX1), whereas in the other case the
AML1 gene was not included in the tandem repetition, showing that apparently similar cytogenetic aberrations may be different at the molecular level.
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