KIR2DS3 is associated with protection against acute myeloid leukemia

Background: Interaction between killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen (HLA) class I molecules is important for regulation of natural killer (NK) cell function. Objective: The aim of this study was to investigate the impact of compound KIR-HLA genotype on susceptibility to acute leukemia. Methods: Cohorts of Iranian patients with acute myeloid leukemia (AML; n=40) and acute lymphoid leukemia (ALL; n=38) were genotyped for seventeen KIR genes and their three major HLA class I ligand groups (C1, C2, Bw4) by a combined polymerase chain reaction-sequence-specific primers (PCR-SSP) assay. The results were compared with those of 200 healthy control individuals. Results: We found a significantly decreased frequency of KIR2DS3 in AML patients compared to control group (12.5 vs. 38, odds ratio=0.23, p=0.0018). Also, the KIR3DS1 was less common in AML group than controls (27.5 vs. 44.5, p=0.0465, not significant after correction). Other analyses including KIR genotypes, distribution and balance of inhibitory and activating KIR+HLA combinations, and coinheritance of activating KIR genes with inhibitory KIR+HLA pairs were not significantly different between leukemia patients and the control group. However, in AML patients a trend toward less activating and more inhibitory KIR-HLA state was observed. Interestingly, this situation was not found in ALL patients and inhibition enhancement through increase of HLA ligands and inhibitory combinations was the main feature in this group. Conclusion: Our findings may suggest a mechanism for escape of leukemic cells from NK cell immunity

Inhibitory killer cell immunoglobulin-like receptor KIR3DL1 in combination with HLA-B Bw4iso protect against Ankylosing spondylitis

Background: The HLA class I molecules serve as ligands for both T cell receptors and killer cell immunoglobulin-like receptors (KIRs). Objective: We investigated the HLA- C and HLA-Bw4 alleles as well as KIRs expression on CD56 positive lymphocytes to evaluate whether these genes and molecules could influence Ankylosing spondylitis (AS) susceptibility, alone or in combination. Methods: We typed 40 AS patients and 40 normal controls for HLA-C asn80 (group 1) and HLA-C lys80 (group 2), HLA-B Bw4thero, HLA-B Bw4iso and HLA-A Bw4 alleles by PCR-SSP method. We also as- sessed the expression of KIR2DL1/2DS1, KIR2DL2/2DL3, KIR3DL1 and KIR2DS4 by flow cytometry. The Pearson chi-square or Fisher exact test was performed for statisti- cal analysis. Results: The frequency of HLA-B Bw4iso but not HLA-B Bw4thero and HLA-A Bw4, ligand for the inhibitory KIR3DL1, was significantly reduced in AS pa- tients as compared with controls (p<0.01). No significant differences were observed in gene carrier frequencies of HLA-C group 1 and 2 between AS and controls. Although no differences were found in the expression of KIR receptors between AS and normal subjects, we found that expression of KIR3DL1 in the presence of HLA Bw4-Biso gene was reduced in patients with AS compared to healthy controls (p<0.009). Conclusion: We conclude that HLA-B Bw4iso, the ligand of inhibitory KIR3DL1, with and without the expression of KIR3DL1 might be involved in protection against AS. Our results suggest that besides the HLA and KIR genotype, expression levels of KIRs may be in- volved in the pathogenesis of AS disease

Exploring cancer register data to find risk factors for recurrence of breast cancer – application of Canonical Correlation Analysis

BACKGROUND: A common approach in exploring register data is to find relationships between outcomes and predictors by using multiple regression analysis (MRA). If there is more than one outcome variable, the analysis must then be repeated, and the results combined in some arbitrary fashion. In contrast, Canonical Correlation Analysis (CCA) has the ability to analyze multiple outcomes at the same time. One essential outcome after breast cancer treatment is recurrence of the disease. It is important to understand the relationship between different predictors and recurrence, including the time interval until recurrence. This study describes the application of CCA to find important predictors for two different outcomes for breast cancer patients, loco-regional recurrence and occurrence of distant metastasis and to decrease the number of variables in the sets of predictors and outcomes without decreasing the predictive strength of the model. METHODS: Data for 637 malignant breast cancer patients admitted in the south-east region of Sweden were analyzed. By using CCA and looking at the structure coefficients (loadings), relationships between tumor specifications and the two outcomes during different time intervals were analyzed and a correlation model was built. RESULTS: The analysis successfully detected known predictors for breast cancer recurrence during the first two years and distant metastasis 2–4 years after diagnosis. Nottingham Histologic Grading (NHG) was the most important predictor, while age of the patient at the time of diagnosis was not an important predictor. CONCLUSION: In cancer registers with high dimensionality, CCA can be used for identifying the importance of risk factors for breast cancer recurrence. This technique can result in a model ready for further processing by data mining methods through reducing the number of variables to important ones

Vibration analysis of viscoelastic single-walled carbon nanotubes resting on a viscoelastic foundation

Vibration responses were investigated for a viscoelastic Single-walled carbon nanotube (visco-SWCNT) resting on a viscoelastic foundation. Based on the nonlocal Euler-Bernoulli beam model, velocity-dependent external damping and Kelvin viscoelastic foundation model, the governing equations were derived. The Transfer function method (TFM) was then used to compute the natural frequencies for general boundary conditions and foundations. In particular, the exact analytical expressions of both complex natural frequencies and critical viscoelastic parameters were obtained for the Kelvin-Voigt visco-SWCNTs with full foundations and certain boundary conditions, and several physically intuitive special cases were discussed. Substantial nonlocal effects, the influence of geometric and physical parameters of the SWCNT and the viscoelastic foundation were observed for the natural frequencies of the supported SWCNTs. The study demonstrates the efficiency and robustness of the developed model for the vibration of the visco-SWCNT-viscoelastic foundation coupling system

Killer Cell Immunoglobulin-like Receptors and their Ligands

The Natural killer (NK) cells are a subset of lymphocytes comprising around 10% of total lymphocytes in peripheral blood. Due to their role in the innate response, NK cells provide a ‘first line of defense’ against infectious agents and cancer and are also thought to play a role in autoimmunity. The killer cell immunoglobulin-like receptors (KIR) are regulatory surface molecules, found on NK cells and on a subset of T lymphocytes. The genes for KIR are present on chromosome 19 in the leukocyte receptor complex and show a major difference for both the type and number of KIR genes present among different ethnic groups. They have been divided into two groups of 2D or 3D, depending on the number of external immunoglobulin domains. The presence of a long cytoplasmic tail with two immune tyrosine-based inhibitory motifs (ITIM) allows the transduction of inhibitory signals and characterizes the inhibitory KIRs (2DL and 3DL), whereas the presence of short cytoplasmic tails corresponds to the activating KIR receptors (2DS and 3DS).These polymorphic receptors interact with specific motifs on human leukocyte antigen (HLA) class I molecules, modulate NK cytolytic activity. Some KIRs are known to interact with HLA-C molecules of target cells, HLA-Bw4 molecules and HLA-A3/11. For some KIRs the corresponding ligands are still unknown

Integration of resource investment problem with quantity discount problem in material ordering for minimizing resource costs of projects

Minimizing the costs in a project is highly tied with the way the required resources are provided. The resource investment problem deals with how to employ the renewable resources such that the related costs are minimized. Furthermore, the material ordering problem alludes to outlining a proper plan for supplying the nonrenewable resources (materials) to minimize the associated costs. The present paper studies the integration of the resource investment problem with the quantity discount problem in material ordering to thoroughly investigate the resource costs of projects in a single circumstance. The integrated model is presented and mathematically formulated. Three hybrid procedures are proposed for the model, each of which includes a genetic algorithm combined with a dynamic programming, a simulated annealing or a particle swarm optimization algorithm. The mathematical formulations of some small instances are solved to be the subject of an exact comparison with hybrid procedures. The proposed procedures are tested on a set of 810 benchmarks known in the literature. The computational experiments reported by algorithms validate the efficiency of the hybrid genetic algorithm and dynamic programming for the model more than other hybrid approaches

The susceptibility to diabetic retinopathy in type 2 diabetic patients of Iran is not affected by the M55V polymorphism of SUMO4

Introduction: Recent reports showed that the small ubiquitin-like modifier 4 (SUMO4) M55V polymorphism is affected development of type 2 diabetes and its complications such as diabetic nephropathy and retinopathy in some populations. In this regard we intend to investigate the impact of M55V polymorphism of SUMO4 on susceptibility to diabetic retinopathy in the type 2 diabetic patients of Iran. Methods: In current study, the control group had included 100 individuals of type 2 diabetic patients of Iran who have not retinopathy, while the patient group had included 100 individuals of type 2 diabetic patients of Iran suffering from retinopathy. We have matched all the confounding factors between patients and controls. The genotyping method was PCR-RFLP to trace a prevalent single nucleotide polymorphism at codon 55 encoding a substitution of methionine to valine (M55V) specified in the SUMO4 gene. Results: Genotype frequency of AA, AG, and GG of SUMO4 were obtained respectively 52, 30, and 18 in the patient group and 44, 36, and 20 in the control group. The frequencies of alleles A and G of SUMO4 were 67 and 33 in the patients with type 2 diabetes having retinopathy and 62 and 38 in the patients with type 2 diabetes without retinopathy. There genotypic and allelic frequencies of SUMO4 were not significantly (p>0.05) different between the patient and the control groups. Conclusions: The findings of the present study showed no correlation between M55V polymorphism of SUMO4 gene and diabetic retinopathy in type 2 diabetes patients of Iran. However, we emphasize that further studies is necessary to clarify the exact role of M55V polymorphism of SUMO4 in diabetic retinopathy in patients with type 2 diabetes

Compound KIR-HLA genotype analyses in the Iranian population by a ovel PCR-SSP assay

Natural killer (NK) cells eliminate infected and transformedcells while still are self-tolerant. Interactions ofthe independently segregating Killer cell immunoglobulin- like receptors (KIR) and human leucocyte antigens(HLA) loci play a critical role in NK cell regulation.Different compound KIR-HLA genotypes can impart different thresholds of activation to the NK-cell repertoire and such genotypic variation has been found to confer altered risk in a number of human diseases including viral infections, autoimmune disorders, reproductionabnormalities and cancers. In this study, wepresented a novel combined KIR-HLA polymerasechain reaction-sequence-specific primers genotypingassay for simultaneous determination of KIR genesand their three major HLA class I ligand groups (C1, C2, and Bw4). Moreover, known inhibitory and activatingKIR + HLA (iKIR + HLA: 2DL2/3 + C1, 2DL1 + C2, 3DL1 + Bw4; and aKIR + HLA: 2DS2 +C1, 2DS1 + C2, 3DS1 + Bw4) combinations as well as co-inheritance of aKIR genes and iKIR + HLA pairs were analysed in a total of 200 unrelated healthy Iranian individuals. All tested subjects had at least one of the three iKIR + HLA pairs and the frequencies of various inhibitory combinations in the study group were: 31.5, three iKIR + HLA pairs, 53.5, two iKIR + HLA pairs, and 15, 0ne iKIR + HLA pair. Furthermore, we revealed that majority of Iranians (69) carry compound genotypes with greater number of inhibitory pairings than activating combinations (iKIR + HLA > aKIR + HLA). Conversely, iKIR + HLA < aKIR (45) was dominant genotype in the study group. We conclude that selective evolutionary pressure has propensity to maintain KIR-HLA genotypes with more inhibitory combinations to guaranteeself-tolerance. In contrast, existence of activating KIR genes without normal endogenous ligands, potentially arms the NK population for competent immunosurveillance and stronger defense against infections. © 2010 Blackwell Publishing Ltd