The role of FOXP3 rs3761548 and rs2294021 polymorphisms in pediatrics acute lymphoblastic leukemia: association with risk and response to therapy

FOXP3 X-linked gene has crucial roles in the development and function of regulatory T cells. We investigated the association of FOXP3 rs3761548, rs3761549 and rs2294021 single nucleotide polymorphisms (SNPs) with acute lymphoblastic leukemia (ALL) susceptibility and response to therapy. Genotyping was performed in 247 patients and 210 healthy subjects. We observed a higher frequency of rs3761548 A carriers and rs2294021 C carriers (p?<?0.04) in male patients, and lower frequencies of rs3761548 AC genotype (p?=?0.04) and rs2294021 CT genotype (p?=?0.01) in female patients compared to controls. ACC (p?=?0.04) and ATC haplotypes (p?=?0.002) were associated with susceptibility to ALL. There was a significant correlation between the genotypes of rs3761548 and rs2294021 SNPs with event-free survival (EFS) and overall survival (OS). The rs3761548 A genotype in male patients was associated with increased risk of relapse (p?<?0.0001), shorter EFS, increased death rate (p?=?0.002) and shorter OS compared to C genotype (p?=?0.001). Similar significant results were observed for the relation of rs2294021 C genotype with response to therapy in male patients. In females, patients with rs3761548 AC genotype had longer EFS (p?=?0.02) and those with rs2294021 CT had longer EFS and OS (p?<?0.005). According to haplotype analysis, patients carrying ACC or ATC haplotypes had the highest number of WBCs and shorter EFS or OS, and patients with CCT haplotype had the lowest number of WBCs and longer EFS or OS. These results provided evidence for the impact of these polymorphisms on susceptibility and response to therapy in children with ALL.

     

Nuclear Localization of the Mitochondrial Factor HIGD1A during Metabolic Stress

Cellular stress responses are frequently governed by the subcellular localization of critical effector proteins. Apoptosis-inducing Factor (AIF) or Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), for example, can translocate from mitochondria to the nucleus, where they modulate apoptotic death pathways. Hypoxia-inducible gene domain 1A (HIGD1A) is a mitochondrial protein regulated by Hypoxia-inducible Factor-1α (HIF1α). Here we show that while HIGD1A resides in mitochondria during physiological hypoxia, severe metabolic stress, such as glucose starvation coupled with hypoxia, in addition to DNA damage induced by etoposide, triggers its nuclear accumulation. We show that nuclear localization of HIGD1A overlaps with that of AIF, and is dependent on the presence of BAX and BAK. Furthermore, we show that AIF and HIGD1A physically interact. Additionally, we demonstrate that nuclear HIGD1A is a potential marker of metabolic stress in vivo, frequently observed in diverse pathological states such as myocardial infarction, hypoxic-ischemic encephalopathy (HIE), and different types of cancer. In summary, we demonstrate a novel nuclear localization of HIGD1A that is commonly observed in human disease processes in vivo.     

BTN3A2 expression in epithelial ovarian cancer is associated with higher tumor infiltrating T cells and a better prognosis

BTN3A2/BT3.2 butyrophilin mRNA expression by tumoral cells was previously identified as a prognostic factor in a small cohort of high grade serous epithelial ovarian cancer (HG-EOC). Here, we evaluated the prognostic value of BT3.2 at the protein level in specimen from 199 HG-EOC patients. As the only known role of butyrophilin proteins is in immune regulation, we evaluated the association between BT3.2 expression and intratumoral infiltration of immune cells by immunohistochemistry with specific antibodies against BT3.2, CD3, CD4, CD8, CD20, CD68 and CD206. Epithelial BT3.2 expression was significantly associated with longer overall survival and lower risk of disease progression (HR?=?0.651, p?=?0.006 and HR?=?0.642, p?=?0.002, respectively) and significantly associated with a higher density of infiltrating T cells, particularly CD4+ cells (0.272, p<0.001). We also observed a strong association between the relative density of CD206+ cells, as evaluated by the ratio of intratumoral CD206+/CD68+ expression, and risk of disease progression (HR?=?1.355 p?=?0.044, respectively). In conclusion, BT3.2 protein is a potential prognostic biomarker for the identification of HG-EOC patients with better outcome. In contrast, high CD206+/CD68+ expression is associated with high risk of disease progression. While the role of BT3.2 is still unknown, our result suggest that BT3.2 expression by epithelial cells may modulates the intratumoral infiltration of immune cells.     

Mitochondrial D-Loop Variation in Persian Multiple Sclerosis Patients: K and A Haplogroups as a Risk Factor!!

Multiple Sclerosis (MS) is a multifocal demyelinating central nervous system disorder in which interplay between genes and the environment are supposed to be involved. Mitochondrial DNA (mtDNA) has the only non-coding regions at the displacement loop (D-loop) region that contains two hypervariable segments (HVS-I and HVS-II) with high polymorphism. mtDNA has already been fully sequenced and many subsequent publications have showed polymorphic sites, haplogroups and haplotypes. Haplogroups could have important implications to understand association between mutability of the mitochondrial genome and disease. To assess relationship between mtDNA haplogroups and MS, we have sequenced the mtDNA HVS-I in 54 MS patients and 100 control subjects. We have found that haplogroups A and K are significantly more abundant in MS patients (P=0.042 for haplogroup A and P=0.0005 for haplogroup K). Thus, these two haplogroups might act synergistically to increase the penetrance of MS disease.     

The Genomic Landscape of TP53 and p53 Annotated High Grade Ovarian Serous Carcinomas from a Defined Founder Population Associated with Patient Outcome

High-grade ovarian serous carcinomas (HGSC) are characterized by TP53 mutations and non-random patterns of chromosomal anomalies, where the nature of the TP53 mutation may correlate with clinical outcome. However, the frequency of common somatic genomic events occurring in HGSCs from demographically defined populations has not been explored. Whole genome SNP array, and TP53 mutation, gene and protein expression analyses were assessed in 87 confirmed HGSC samples with clinical correlates from French Canadians, a population exhibiting strong founder effects, and results were compared with independent reports describing similar analyses from unselected populations. TP53 mutations were identified in 91% of HGSCs. Anomalies observed in more than 50% of TP53 mutation-positive HGSCs involved gains of 3q, 8q and 20q, and losses of 4q, 5q, 6q, 8p, 13q, 16q, 17p, 17q, 22q and Xp. Nearly 400 regions of non-overlapping amplification or deletion were identified, where 178 amplifications and 98 deletions involved known genes. The subgroup expressing mutant p53 protein exhibited significantly prolonged overall and disease-free survival as compared with the p53 protein null subgroup. Interestingly, a comparative analysis of genomic landscapes revealed a significant enrichment of gains involving 1q, 8q, and 12p intervals in the subgroup expressing mutant p53 protein as compared with the p53 protein null subgroup. Although the findings show that the frequency of TP53 mutations and the genomic landscapes observed in French Canadian samples were similar to those reported for samples from unselected populations, there were differences in the magnitude of global gains/losses of specific chromosomal arms and in the spectrum of amplifications and deletions involving focal regions in individual samples. The findings from our comparative genomic analyses also support the notion that there may be biological differences between HGSCs that could be related to the nature of the TP53 mutation.     

In vitro protoscolicidal effects of hypertonic glucose on protoscolices of hydatid cyst

To evaluate the protoscolicidal effects of various concentrations of hypertonic glucose, live protoscolices of sheep were exposed to 10%, 15%, 25% and 50% glucose solutions. Cetrimide (0.5%), silver nitrate (0.5%) and hypertonic saline (20%) were used as positive controls, while physiological saline was used as a negative control. After 1, 2 and 5 min, the protoscolicidal effects were determined by 1% eosin. A 25% glucose solution had no significant protoscolicidal effect. However, a 50% glucose solution revealed higher protoscolicidal effect than 0.5% silver nitrate but weaker effect than 0.5% cetrimide; the effect was comparable with that of 20% hypertonic saline. The results showed that hypertonic glucose solution is highly effective in killing protoscolices of Echinococcus granulosus in vitro.     

Familial resemblance of body composition,physical activity,and resting metabolic rate in pre-school children

Background:

Although parental obesity is a well-established predisposing factor for the development of obesity, associations between regional body compositions, resting metabolic rates (RMR), and physical activity (PA) of parents and their pre-school children remain unknown. The objective of this study was to investigate parent-child correlations for total and regional body compositions, resting energy expenditures, and physical activity.

Methods:

Participants were 89 children aged 2-6 years and their parents, consisting of 61 families. Resting metabolic rate was assessed using indirect calorimetry. Total and regional body compositions were measured by both dual energy X-ray absorptiometry (DXA) and deuterium dilution. Physical activity was assessed by an accelerometer.

Results:

There was a significant parent-offspring regression for total fat free mass (FFM) between children and their mothers (P=0.02), fathers (P=0.02), and mid-parent (average of father and mother value) (P=0.002) when measured by DXA. The same was true for fat mass (FM) between children and mothers (P<0.01), fathers (P=0.02), and mid-parent (P=0.001). There was no significant association between children and parents for physical activity during the entire week, weekend, weekdays, and different parts of days, except for morning activity, which was positively related to the mothers’ morning activities (P<0.01) and mid-parent (P=0.009). No association was found between RMR of children and parents before and after correction for FFM and FM.

Conclusion:

These data suggest a familial resemblance for total body composition between children and their parents. Our data showed no familial resemblance for PA and RMR between children and their parents. Key Words: Obesity, Familial resemblance, Children, Resting metabolic rate, Physical activity     

Changes to the viscoelastic properties of brain tissue after traumatic axonal injury

While it has been shown that repetitive mild brain injuries can cause cumulative damage to the brain, changes to the mechanical properties of brain tissue at large deformations were also noted in the literature. The goal of this study was to show that the viscoelastic properties of brain tissue significantly change after traumatic axonal injury (TAI). An impact acceleration model was used to create TAI in the rat brainstem which was quantified with an immunohistochemistry technique at the ponto-medullary junction (PmJ) and pyramidal decussation (PDx). The viscoelastic properties at these two points with and without preconditioning were characterized using an indentation technique combined with finite element analysis and a comparison was made between injured and uninjured specimens, which revealed statistically significant reduction in the instantaneous elastic force at PDx where the brain tissue sustained a significantly higher level of injury. The result of this study can be used to characterize a damage function for the brain tissue undergoing large deformation.