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- 1National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation (HMC), Doha, Qatar [2]
- 3Medical Research Centre, HMC, Doha, Qatar [2]
- Chief Executive Officer, Women's Wellness and Research Centre, Hamad Medical Corporation, Doha, Qatar [2]
- Department of Obstetrics and Gynecology, Women's Wellness and Research Centre, Hamad Medical Corporation, Doha Qatar. *Email: [email protected] [2]
- Department of Pediatrics and Neonatology, Women's Wellness and Research Centre, Hamad Medical Corporation, Doha, Qatar [2]
- Department of Research, Women's Wellness and Research Centre, Hamad Medical Corporation, Doha Qatar [2]
- 2Faculty of Health and Social Care Sciences, Kingston University and St George's University of London, United Kingdom [1]
- 2Qatar Medical Genetics Center, Hamad General Hospital (HGH), HMC, Doha, Qatar [1]
- 4Faculty of Health and Social Care Sciences, Kingston University and St George's University of London, London, United Kingdom [1]
- Department of Obstetrics and Gynecology, Sidra Medicine, Doha Qatar [1]
- Hmc- Qmgc/ncccr, Doha, Qatar [1]
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Induction Of Hydroxyurea-Mediated Altered Gene Expression-Like Pattern In Sickle Cell Anaemia Erythroid Cells From Qatari Populations.
Background: Sickle Cell Anaemia (SCA) is a genetically-inherited blood disorder caused by the occurrence of a point mutation in the bases coding for the sixth amino-acid of the β-chain of haemoglobin. The presence of Fetal Haemoglobin (HbF) in blood is known to show a number of beneficial effects in improving the conditions of SCA. Hence clinical symptoms of SCA arise only after HbF levels drop. HbF is synthesized by the HBG1 (gamma-globin) gene. From birth there is a gradual shift from fetal to adult haemoglobin triggered by the downregulation of the HBG1 gene and the upregulation of the HBB gene. Rationale: Hydroyxurea has been widely evaluated in the treatment of SCA for its ability to induce synthesis of HbF by reactivating the expression of the HBG1 gene. It functions by repressing the activity of various transcription factors involved in the downregulation of the HBG1 gene during transition to adult haemoglobin. However hydroxyurea has proven to be potentially toxic in a number of cases and may also carry a possibility of long term carcinogenicity. Therefore it is administered under restriction and may not be used in the treatment of pregnant women and children. In this study an attempt is made to identify and characterise the altered gene expression pattern caused by hydroxyurea treatment through Differential Display Reverse Transcriptase PCR (DDRT-PCR) and Real Time PCR (Q-PCR). Further the phenomenon depicting the repression of the transcription factors leading to the reactivation of HBG1 gene will be reproduced using techniques of RNA interference (RNAi) and antisense. Objective: To reproduce the altered genetic conditions produced by Hydroxyurea treatment for the in-vitro induction of HbF using molecular genetic techniques. Methods: Blood is obtained from SCA patients at diagnosis and after treatment with hydroxyurea. Erythroid Progenitor cells are purified from the collected blood using the EasySep™ Human progenitor cell enrichment kit. Cells are then cultured in a suitable medium and maintained for further analysis. Treatment with hydroxyurea is performed at varying doses at different intervals of time. The evaluation of gene expression is carried out through the generation of c-DNA through a reverse transcriptase PCR cycle followed by Q-PCR for identification and quantification. Results & Conclusion: Buffy coats containing mononuclear cells were purified from peripheral blood obtained from SCA patients through density-gradient centrifugation. Further erythroid progenitor cells were successfully isolated and maintained in culture for variable periods of time. Currently mRNA expression analysis is ongoing through the use of reverse transcriptase PCR protocols. If proven successful this technique holds a promising future scope; as molecular genetic techniques could be used to reproduce the effects of hydroxyurea without the actual administration of the drug. Thus the toxicity issues of the drug are avoided while also making it available to all classes of patients including pregnant women and children.
Maternal and neonatal outcomes associated with multiple repeat cesarean deliveries: A registry-based study from Qatar
Background: Cesarean delivery (CD) is associated with increased maternal and neonatal morbidity compared to vaginal delivery particularly in cases classified as emergency procedures or when there are multiple CDs. This retrospective cohort study aims to examine the incidence of maternal and neonatal complications in women with multiple CDs.Methods: This study used data from a national perinatal database obtained from a single tertiary maternity care hospital. Women who delivered a singleton live birth after 24 weeks of gestation by CD were stratified into five groups based on the number of CDs with the last group having five or more CDs. The women were divided into those with five or more CDs (Group 5) versus those with fewer than five (Groups 1 to 4). The maternal outcomes included intra-operative surgical complications blood loss and intensive care unit (ICU) admission. The neonatal outcomes included preterm birth neonatal ICU (NICU) admission respiratory distress syndrome (RDS) and perinatal death.Results: Of the 6316 women in the study 2608 (41.3%) had a primary CD. 30.3% 17.5% and 7.3% of the cohort had their second third and fourth CDs respectively. Women undergoing the 5th CD and above formed the remaining 3.5% (227). Women in Group 5 had the highest risk of suffering a surgical complication (3.1% p = 0.015) and postpartum hemorrhage (7.5% p = 0.010). 24% of babies in Group 5 were born preterm (p < 0.001). They also had a 3.5 times higher risk of having a surgical complication (RR = 3.5 95% CI 1.6-7.6 p = 0.002) a 1.8 times higher risk of developing postpartum hemorrhage (RR = 1.8 95% CI 1.1-2.9 p = 0.014) a 1.7 times higher risk of delivering between 32-37 weeks of gestation (RR = 1.7 95% CI 1.3-2.2 p < 0.001) a higher risk of the baby getting admitted to NICU (RR = 1.3 95% CI 1.0-1.6 p = 0.038) and developing RDS (RR = 1.5 95% CI 1.2-2.0 p = 0.002) compared to Groups 1-4. The risks of neonatal outcomes such as NICU admission (RR 2.9 95% CI 2.1-4.0) and RDS (RR 3.5 95% CI 2.3-5.5) were much higher in elective CDs performed at term compared to preterm births (p < 0.001 for both).Conclusion: Maternal morbidity significantly increases with the increasing number of CD. The increased risk of RDS and NICU admissions in the neonate with multiple CDs reflects lower gestational age and birthweight in these groups—consideration of preoperative steroids for lung maturation in these women to reduce neonatal morbidity warrants further discussion.
Molecular Monitoring of patients with Chronic Myeloid Leukemia (CML) in the state of Qatar: Optimization of Techniques and Response to Imatinib
Most cases of chronic myeloid leukemia (CML) are associated with the presence of BCR-ABL1 fusion gene; a molecular anomaly that introduced targeting therapy to CML. This study was setup primarily to optimize the real-time quantification detection of BCR-ABL1 transcripts in order to pave the way for using this method as a diagnostic tool to support the clinical management of CML patients in Qatar.
A secondary objective was to evaluate the response of CML patients to Imatinib (IM) and exploit adaption of this technique as an indicator of emerging drug resistance reported in Qatar.
Peripheral blood (PB) samples from 26 CML patients receiving Imatinib were analysed via serial Real-time quantitative polymerase chain reaction (RT-qPCR) to monitor the ratio of BCR-ABL1 to normal ABL1 transcripts. EuropeanLeukemia Net (ELN) 2006 and 2009 guidelines were employed to assess the molecular response to Imatinib.
For patients to be classified as optimal responders major molecular response (MMR) had to be achieved by 18 months of treatment.1 Patients responding to Imatinib achieved major molecular response (MMR) during the 1st year of treatment; while patients who resisted Imatinib treatment did not achieve any molecular response within this time frame.
This was the first molecular study to evaluate the molecular response of CML patients (citizens and residents) to IM in Qatar.
Impact of bariatric surgery on maternal gestational weight gain and pregnancy outcomes in women with obesity: A population-based cohort study from Qatar
Background: Bariatric surgery is performed in obese women of reproductive age to help achieve a healthy prepregnancy weight to reduce the complications associated with obesity in pregnancy. However these procedures can impact maternal nutrition and gestational weight gain (GWG). This study evaluates the maternal and neonatal outcomes in women with prepregnancy bariatric surgery and determines the impact on GWG. Methods: This study included 24 weeks gestation or more pregnancies with a maternal BMI at delivery of 30 kg/m2 or more. It was categorized into two groups based on whether they had prepregnancy bariatric surgery (exposed) or not (unexposed). The outcomes included gestational diabetes (GDM) gestational hypertension (GHT) mode of delivery preterm birth (PTB) GWG birthweight (BW) and customized BW centiles low birthweight (LBW) congenital anomalies and admission to the neonatal intensive unit (NICU). Categorization was also done based on the adequacy of GWG (low adequate and excess). Results: A total of 8323 women were included in the study 194 of whom had prepregnancy bariatric surgery. After adjusting for confounders the exposed group had a mean GWG 1.33 kg higher than the unexposed group (95% CI 0.55-2.13 p = 0.001). The exposed group had higher odds of PTB (aOR 1.78 95% CI 1.16-2.74 p = 0.008) CD (aOR 6.52 95% CI 4.28-9.93 p < 0.001) LBW in term babies (aOR 2.60 95% CI 1.34-5.03 p = 0.005) congenital anomalies (aOR 2.64 95% CI 1.21-5.77 p = 0.015) low APGAR score (aOR 3.75 95% CI 1.12-12.5 p = 0.032) and 80.4g lesser birthweight (95% CI -153.0 -5.8; p = 0.034). More women in the low GWG category had LBW babies (28.6% versus 6.7% in the high GWG group p = 0.033) lowest mean BW and median BW centiles (2775 grams versus 3289 grams in the high GWG group p = 0.004 and 57.5% versus 74.5% in the high GWG group p = 0.040 respectively). Conclusion: The findings of this study highlight differences in perinatal outcomes such as preterm birth low birth weight congenital anomalies cesarean deliveries and gestational weight gain between post-bariatric women and controls. These insights can help inform the planning and provision of appropriate maternity care to enhance patient safety and outcomes. The results of this study can also guide the counseling of reproductive age-group women who are planning to undergo bariatric surgery.
Studying the impact of presence of point mutation, insertion mutation and additional chromosomal abnormalities in chronic myeloid leukemia patients treated with imatinib mesylate in the State of Qatar
Background: Imatinib is failing as a first line treatment in more than 40% of chronic myeloid leukemia (CML) patients in Qatar. We thus investigated ABL1 kinase domain mutations and additional chromosomal abnormalities (ACAs) as underlying mechanisms to explain this high rate of treatment failure. Methods: Between November 2006 and December 2011 all CML patients in Qatar were studied for BCR-ABL1 kinase domain mutations and ACAs. Total RNA was extracted and cDNA was produced via reverse transcriptase polymerase chain reaction (RT-PCR). PCR was used with special precautions to avoid amplification of wild type ABL1; the ABL1 kinase domain was then screened for mutations by direct DNA sequencing technology to detect the emergence of mutant clone.
Cytogenetic analysis of bone marrow (BM) metaphases and fluorescence in situ hybridization (FISH) of peripheral blood (PB) and BM interphases were performed according to standard protocols. European Leukemia Net (ELN) response criteria were employed to identify the failing cases. Results: 26 out of 33 CML patients were eligible for the study 22 CP and 4 AP. 14 failed Imatinib treatment 2 had BCR-ABL1 kinase domain mutations; one patient had the G1739A mutation which leads to the exchange of glutamic acid at position 459 to lysine (E459K) (rs1064156) in the c-terminal loop while the other patient had a unique insertion of three nucleotides (AAG) at position 1432 which adds an amino acid Lysine to position 356 of the catalytic domain and a complex karyotyping at diagnosis 6 had additional chromosomal abnormalities as an underlying mechanism of resistance 4 patients had no identifiable cause of resistance and 2 patients were intolerant to treatment. There was a significant difference in median overall survival between patients with Ph chromosome only and patients with ACAs. Conclusions: In this study as we continued observing CML patients for nearly 5 years the Imatinib failure reached as high as 54%. The resistance rate observed in Qatar is still higher than that reported by the IRIS study which is as high as 35%. In our cohort of CML patients point mutation and unique tri-nucleotide insertions were identified. However these mutations could explain only 14% of treatment failure. Additional chromosomal abnormalities were the most common cause of Imatinib failure in our patients' cohort and were documented in 50% of cases. 14% of patients stopped IM due to intolerance; and the mechanisms of resistance remained unknown in 28% of patients. Other causes such as patients' adherence to Imatitinb is being prospectively investigated.
Identifying Novel Mutations In Familial Myeloproliferative Neoplasms Patients In The State Of Qatar Via Targeted Exome Sequencing Approach
Background: Polycythemia Vera (PV) Essential Thrombocytosis (ET) & Primary Myelofibrosis (PMF) are Philadelphia negative Myeloproliferative Neoplasms (MPNs) characterized by overproduction of one or more myeloid cell lineages. MPNs are associated with the presence JAK2 V617F mutation in 95% of PV & 50% of ET & PMF patients. Several molecular methods such as RQ-PCR HRM & Sequencing are currently used to detect common mutations. However there are still significant numbers of MPNs are negative to the most common genetic anomalies. The advent of Next Generation Sequencing (NGS) gives the opportunity to study relevant mutations in several genes. Aim: Utilizing NGS to identify potential genetic anomalies causing familial MPNs patients in Qatar. Methods: 6 MPNs patients from consanguineous families & 5 healthy individuals were consented into the study gDNA was extracted & used for multiplex amplification of amplicons targeting cancer associated mutations in 28 key genes using the Ion AmpliSeq Kit. NGS was performed via the Ion Torrent using the 318 chip & data was analyzed with the Torrent Suite. The confirmation of NGS data was done by RQ-PCR or Sequencing. Results: NGS identified novel deleterious mutations in MPNs patients. Out of 6 familial cases 5 patients (P1- P5) were ET & 1 patient (P6) was PV. P1 had JAK2 V617F ASXL1 T600P CBFB G180S THPO S184R & ITGA2 R76Q P2 had JAK2 V617F MPL A554G & ATM F582L the other three Patients (P3 P4 & P5) had CLAR K385fs*47 & one PV patient (P6) had TYK2 E1163G ASXL1 P808H PDGFRB P4L TERT G300fs. In patients & healthy individuals mutations/SNVs such as MPL P106L K553N SH2B3 L476F ATM F1036F KIT N564S & TET2 T730R were also found Discussion & conclusion: In this study several deleterious somatic/germ-line mutations/SNVs were identified using Targeted Exome Sequencing approach. A complex combination of mutations occurred in ET patients & coexistence of several oncogenic events occurred in PV patient. This finding may also suggest that the MPNs phenotype may depend on presence of other mutations. It is worth to mention that the presence of ATM variant in P2 is associated with increased risk of CLL. Somatic CALR type-2 mutation was identified in 3 ET (nonmutated JAK2 or MPL) patients. This mutation is 5-bp TTGTC insertion in exon 9 that generates a mutant protein with a novel C-terminal (p.K385fs*47). In patients & healthy individuals a heterozygous germ-line mutation in exon 3 of the MPL gene (MPL P106L) has been observed and previously described as a rare autosomal-dominant disorder. However this mutation is considered to be frequent in Arabic populations also several unreported variants of uncertain significance were identified. Our finding suggested that familial MPNs patients in Qatari tribes have several potential disease- associated variants/mutations which represent a unique interest for the scientific community worldwide and present an unprecedented opportunity for local and international collaborations to carry out WES in society with its unique coherence and genetic pool (founder effect) this would offer invaluable resources to unravel the genetic etiology and pathogenesis delineate the mechanisms behind MPNs phenotypic diversity.