MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia

Background

MicroRNA regulate the activity of protein-coding genes including those involved in hematopoietic cancers. The aim of the current study was to explore which microRNA are unique for seven different subtypes of pediatric acute lymphoblastic leukemia.

Design and Methods

Expression levels of 397 microRNA (including novel microRNA) were measured by quantitative real-time polymerase chain reaction in 81 cases of pediatric leukemia and 17 normal hematopoietic control cases.

Results

All major subtypes of acute lymphoblastic leukemia, i.e. T-cell, MLL-rearranged, TEL-AML1-positive, E2A-PBX1-positive and hyperdiploid acute lymphoblastic leukemia, with the exception of BCR-ABL-positive and ‘B-other’ acute lymphoblastic leukemias (defined as precursor B-cell acute lymphoblastic leukemia not carrying the foregoing cytogenetic aberrations), were found to have unique microRNA-signatures that differed from each other and from those of healthy hematopoietic cells. Strikingly, the microRNA signature of TEL-AML1-positive and hyperdiploid cases partly overlapped, which may suggest a common underlying biology. Moreover, aberrant down-regulation of let-7b (~70-fold) in MLL-rearranged acute lymphoblastic leukemia was linked to up-regulation of oncoprotein c-Myc (P_FDR<0.0001). Resistance to vincristine and daunorubicin was characterized by an approximately 20-fold up-regulation of miR-125b, miR-99a and miR-100 (P_FDR≤0.002). No discriminative microRNA were found for prednisolone response and only one microRNA was linked to resistance to L-asparaginase. A combined expression profile based on 14 microRNA that were individually associated with prognosis, was highly predictive of clinical outcome in pediatric acute lymphoblastic leukemia (5-year disease-free survival of 89.4%±7% versus 60.8±12%, P=0.001).

Conclusions

Genetic subtypes and drug-resistant leukemic cells display characteristic microRNA signatures in pediatric acute lymphoblastic leukemia. Functional studies of discriminative and prognostically important microRNA may provide new insights into the biology of pediatric acute lymphoblastic leukemia.     

Caring for dying and meeting death: experiences of Iranian and Swedish nurses

Objective:

Our world is rapidly becoming a global community, which creates a need to further understand the universal phenomena of death and professional caring for dying persons. This study thus was conducted to describe the meaning of nurses’ experiences of caring for dying people in the cultural contexts of Iran and Sweden.

Materials and Methods:

Using a phenomenological approach, phenomenon of caring for dying people was studied. Eight registered nurses who were working in oncology units in Tehran, Iran and eight registered nurses working in hospital and home care in North part of Sweden were interviewed. The interviews were analyzed using the principles of phenomenological hermeneutics.

Results:

The findings were formulated based on two themes included: (1) “Sharing space and time to be lost”, and (2) “Caring is a learning process.

Conclusions:

The results showed that being with dying people raise an ethical demand that calls for personal and professional response, regardless of sex, culture or context. The physical and organizational context must be supportive and enable nurses to stand up to the demands of close relationships. Specific units and teamwork across various personnel seem to be a solution that is missing in Iran.     

Role of dominant versus non-dominant hand position during uninterrupted chest compression CPR by novice rescuers: a randomized double-blind crossover study

BACKGROUND: Previous research has suggested improved quality of chest compressions when the dominant hand was in contact with the sternum. However, the study was in health care professionals and during conventional chest compression-ventilation CPR. The aim of this study was to test the hypothesis, in null form, that the quality of external chest compressions (ECC) in novice rescuers during 5min of uninterrupted chest compression CPR (UCC-CPR) is independent of the hand in contact with the sternum. Confirmation of the hypothesis would allow the use of either hand by the novice rescuers during UCC-CPR. METHODS: Fifty-nine first year public heath students participated in this randomised double-blind crossover study. After completion of a standard adult BLS course, they performed single rescuer adult UCC-CPR for 5 min on a recording Resusci Anne. One week later they changed the hand of contact with the sternum while performing ECC. The quality of ECC was recorded by the skill meter for the dominant and non-dominant hand during 5 min ECC. RESULTS: The total number of correct chest compressions in the dominant hand group (DH), mean 183+/-152, was not statistically different from the non-dominant hand group (NH), mean 152+/-135 (P=0.09). The number of ECC with inadequate depth in the DH group, mean 197+/-174 and NH group, mean 196+/-173 were comparable (P=0.1). The incidence of ECC exceeding the recommended depth in the DH group, mean 51+/-110 and NH group, mean 32+/-75 were comparable (P=0.1). CONCLUSIONS: Although there is a trend to increased incidence of correct chest compressions with positioning the dominant hand in contact with the sternum, it does not reach statistical significance during UCC-CPR by the novice rescuers for 5 min.     

Correlation of sulfur mustard exposure and tobacco use with expression (immunoreactivity) of p53 protein in bronchial epithelium of Iranian "mustard lung" patients

A unique chronic obstructive pulmonary disease (COPD), provisionally called "mustard lung", which occurs as a late complication of sulfur mustard (SM) exposure among SM-exposed Iranians, is presently poorly characterized. This investigation evaluates p53 immunoreactivity in bronchial epithelium of individuals with histories of tobacco use and/or SM exposure, as a tool to help define mustard lung. In this study, 68 COPD patients were segregated into two groups, 35 mustard-exposed patients (including 8 smokers) and 33 unexposed patients (including 16 smokers). Disease severity was assessed with pulmonary function tests. p53 protein in bronchial tissue obtained as biopsies was quantitated by immunostaining. Among nonsmokers, 41.2% of unexposed subjects and 14.8% of exposed subjects expressed p53. Among smokers, 25% of the unexposed group and 50% of the exposed group expressed the protein. Initial data trends suggest an additive contribution of SM exposure and smoking to p53 immunoreactivity. These results illustrate the use of p53 immunoreactivity in the characterization of COPD, including mustard lung.     

Multiple sclerosis and amyotrophic lateral sclerosis: is there a link?

To date, there are no reports studying the rate of amyotrophic lateral sclerosis (ALS) in relatives of multiple sclerosis (MS) patients and vice versa. This study was designed to look into this issue using two population-based databases of MS and ALS in Isfahan province of Iran. We have searched for any first, second or third degree familial kinship between the Isfahan MS Society database and Isfahan ALS population. We compared the rate of ALS among the population of first degree relatives of MS patients, with the crude prevalence of ALS in the general population of Isfahan. On the other hand, a reverse analysis was carried out to compare the prevalence of MS in Isfahan with its rate amongst the first degree relatives of ALS patients. We found 10 families among which five had first degree kinship. The rate of the diseases was significantly higher in both comparisons among the family members (p < 0.00001) and an odds ratios of more than 67 in both calculations showed a several-fold increase of ALS occurrence in the first degree relatives of MS patients and vice versa. In our study relatives of MS patients were significantly more prone to ALS and vice versa. This could give clues about the common features that the two disease share. Both diseases have an environmental and genetic component and these results mostly point toward genetic similarities.     

Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3

As part of a large-scale, systematic effort to unravel the molecular causes of autosomal recessive mental retardation, we have previously described a novel syndrome consisting of mental retardation, coloboma, cataract and kyphosis (Kahrizi syndrome, OMIM 612713) and mapped the underlying gene to a 10.4-Mb interval near the centromere on chromosome 4. By combining array-based exon enrichment and next generation sequencing, we have now identified a homozygous frameshift mutation (c.203dupC; p.Phe69LeufsX2) in the gene for steroid 5α-reductase type 3 (SRD5A3) as the disease-causing change in this interval. Recent evidence indicates that this enzyme is required for the conversion of polyprenol to dolichol, a step that is essential for N-linked protein glycosylation. Independently, another group has recently observed SRD5A3 mutations in several families with a type 1 congenital disorder of glycosylation (CDG type Ix, OMIM 212067), mental retardation, cerebellar ataxia and eye disorders. Our results show that Kahrizi syndrome and this CDG Ix subtype are allelic disorders, and they illustrate the potential of next-generation sequencing strategies for the elucidation of single gene defects.     

Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss

Mutations in GJB2, encoding connexin 26 (Cx26), cause both autosomal dominant and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNA3 and DFNB1 loci, respectively. Most of the over 100 described GJB2 mutations cause ARNSHL. Only a minority has been associated with autosomal dominant hearing loss. In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn). Both families were ascertained from the same village in northern Iran consistent with a founder effect. This finding implicates the D46N missense mutation in Cx26 as a common cause of deafness in this part of Iran mandating mutation screening of GJB2 for D46N in all persons with hearing loss who originate from this geographic region.     

Mutation spectrum of phenylketonuria in Iranian population

Identification of molecular basis of phenylketonuria (PKU) in Iran has been accomplished through the analysis of 248 unrelated chromosomes from 124 Iranian classic PKU subjects. Phenylalanine hydroxylase (PAH) gene mutations were analyzed through a combined approach in which p.S67P, p.R252W, p.R261Q, p.R261X, p.L333F, IVS10-11G>A, IVS11+1G>C, p.L364del, p.R408Q and p.R408W mutations were first screened by PCR of PAH gene exons 3, 7, 10, 11 and 12, followed by digestion with the appropriate digestion enzymes. Subsequently SSCP analysis for exons 2, 6, 7 and 11 of the PAH gene and finally, sequencing of 13 PAH gene exons have been used to study uncharacterized PKU chromosomes. 26 different mutations were found. The predominant mutation in this population sample was IVS10-11G>A, with a frequency of 24.6%. Nine mutations (IVS10-11G>A, p.R261Q, p.P281L, IVS11+1G>C, p.K363>NFS, p.R243X, IVS2+5G>C, p.R261X and p.R252W) represent almost 84% of all PKU chromosomes studied. IVS10-11G>A mutation is the major PKU-causing mutation throughout the Mediterranean region. The finding of the high prevalence of this mutation in Iranian population is consistent with the historical and geographical links between Iranian and Mediterranean populations.     

The effect of antagonization of orexin 1 receptors in CA1 and dentate gyrus regions on memory processing in passive avoidance task

The hippocampal formation plays an essential role in associative learning like passive avoidance (PA) learning. It has been shown; orexin-containing terminals and orexin receptors densely are distributed in the hippocampal formation. We have previously demonstrated that antagonization of orexin 1 receptor (OX1R) in CA1 region of hippocampus and dentate gyrus (DG) impaired spatial memory processing. Although, there are few studies concerning function of orexinergic system on memory processing in PA task, but there is no study about physiological function of OX1R on this process. To address this, the OX1R antagonist, SB-334867-A, was injected into DG or CA1 regions of hippocampus and evaluated the influence of OX1R antagonization on acquisition, consolidation and retrieval in PA task. Our results show that, SB-334867-A administration into CA1 region impaired memory retrieval but not PA acquisition and consolidation. However, SB-334867-A administration into DG region impaired acquisition and consolidation but not PA memory retrieval. Therefore, it seems that endogenous orexins play an important role in learning and memory in the rat through OX1Rs.