Association of HSD17B13 rs72613567: TA allelic variant with liver disease: review and meta-analysis

Background To assess the association of HSD17B13 rs72613567:TA allelic variant with liver disease, we performed the current review and meta-analysis. Methods Seven studies were identified by a search of CNKI,CBM,MEDLINE, PubMed, EMBASE, and CENTRAL databases from inception to November 2021. Odds ratios (ORs) with 95% confidence interval (CI) were calculated using random effects model or fixed effects model based on the between-study heterogeneity. The Stata 14.0 software was employed for data analysis. Results Statistical analysis showed that the HSD17B13 rs72613567:TA allelic variant can decrease the risk of hepatocellular carcinoma(HCC) in nonalcoholic fatty liver disease (NAFLD) patients, alcoholic fatty liver disease (ALD) patients and viral hepatitis patients (TA vs T OR = 0.766, 95% CI = 0.682–0.860, P = 0.000; TATA + TAT vs TT OR = 0.755, 95% CI = 0.645–0.885, P = 0.001) or healthy controls(TA vs T OR = 0.649, 95% CI = 0.431–0.977, P = 0.038). Besides, the HSD17B13 rs72613567:TA allelic variant can also provide protection from nonalcoholic fatty liver disease (NAFLD) not only in entire population (TA vs T OR = 0.669, 95% CI = 0.524–0.856, P = 0.001) but also in healthy people (TA vs T OR = 0.600, 95% CI = 0.464–0.777, P = 0.000). No significant publication bias found in this airticle. Conclusion The present findings suggest HSD17B13 rs72613567:TA allelic variant can reduce the risk of HCC and NAFLD in the entire population studied.

Genetic Landscape and Clonal Evolution Patterns of CEBPA-Mutated Acute Myeloid Leukaemia Based on Next-Generation Sequencing: A Retrospective Analysis

Introduction Although CCAAT/enhancer binding protein alpha double mutated (CEBPADM) acute myeloid leukemia (AML) is considered a low-risk form of AML according to 2017 ELN recommendations, relapse remains a major cause of death. To assess the broader prognostic impact of other cancer-associated genes, we sequenced a panel of 40 myeloid disorders-related genes in a 25 patient cohort. Methods 16 CEBPADM AML diagnosis samples along with 9 CEBPAsingle mutated (SM) were analyzed by targeted next-generation sequencing (Ion Torrent) using Oncomine Myeloid Research Assay. 4 CEBPADM and 2 CEBPASM AML relapse samples were analyzed as well. All patients received intensive chemotherapy according to 2017 ELN recommendations. Results With a median follow-up of 3.2 years (range 0.4-12) 5y OS was 61% and 14% for CEBPADM and CEBPASM patients respectively. Overall, a median of 3 concurrent mutations were present at diagnosis, slightly more in CEBPA SM patients (4 vs 3 in CEBPA DMpatients). The number of somatic mutations influenced both PFS and OS (p = 0.04 and p < 0.01 respectively) independently of CEBPA mutational status. Each single unitary increase in the number of mutations increased the hazard for death of 27.7% (95% CI: -1.4-+65; p = 0.064) while passing from 4 to 5 mutations increased the odds of death by 367%. 5y OS in patients with 5 or more concurrent mutation was 14.3% vs 61.8% in patients with less than 5 co-mutated genes; 5y PFS was 0% vs 38.6%. Mutational landscape of CEBPADMand CEBPASMAML differed significantly, with GATA2, FLT3, DNMT3A and TET2 being the most frequently mutated genes in CEBPADM vs NPM1, FLT3, DNMT3A and WT1 in CEBPASM patients. NPM1(77.8% vs 6.7%; p < 0.01) and ASXL1 mutations (44.4% vs 0%; p = 0.02) were more frequent in CEBPASM patients, confirming they are mutually exclusive with CEBPA biallelic lesions. DNA methylation was the most frequently mutated pathway in biallelic patients (87%) while chromatin/cohesin complex (88%) was the most frequently mutated one in CEBPA monoallelic patients. Mutations of CEBPA, NPM1, DNMT3A, WT1, STAG2, TET2, ASXL1, IDH2, SRSF2, CALR, PRPF8, NF1, TP53, RUNX1 had the highest median variant allele frequency (VAF), more often representing founding mutations. GATA2, IDH1, KRAS, BCOR, MPL, IKZ2F1 and PTPN11 had a more borderline median VAF, variably being clonal or subclonal. Mutations in the 3 tyrosine kinases genes FLT3-ITD , CSF3R, NRAS were only subclonal. Mutations in WT1 and FLT3 were associated with increased relapse rate (p = 0.02 and p = 0.01 respectively), while patients with GATA2 mutations had a strong trend towards better 5y OS (83% vs 32%, p = 0.053). We also identified a not previously described allelic variant in the SH2B3 gene (ATGGGG/A INDEL) with an overall prevalence in our population of 58.3% (46.7% of CEBPA DM and 77.8% of CEBPA SMpatients). Patients with the SH2B3allelic variant had a significantly lower bone marrow blast percentage at diagnosis (p = 0.014) and a strong trend towards a higher number of concurrent mutations (p = 0.056). Moreover, when present at diagnosis, SH2B3 variant persisted at relapse with the same VAF. By real time PCR we demonstrated that this SH2B3 allelic variant leads to a dramatic reduction of the corresponding transcript. This gene encodes for a negative regulator of many crucial signaling pathways (SCF/c-KIT, erythropoietin/JAK2, thrombopoietin/MPL WT/ W515L, JAK2 WT/ V617F, GM-CSFR and FLT3-WT/ITD) of the hematopoietic stem cell. Matched diagnosis and relapse samples analysis suggested different features of clonal evolution: while mutations of SH2B3, WT1, DNMT3A, NPM1, and IDH1 consistently persisted at relapse, CEBPA and GATA2 mutations were unstable during disease course. ZRSR2 and PRPF8 mutations were found in relapse samples only. Summary Our study offers insights into the genetic landscape of CEBPADM mutated AML as compared to CEBPASM AML, highlighting the contribution of NGS to risk stratification. In fact, our data show that the number and the type of concurrent mutation has a prognostic impact, possibly identifying patients eligible to first line allogeneic stem cell transplantation. We identified an allelic variant of SH2B3 that had never been functionally characterized nor associated with AML and that could represent a marker for genetic instability and a potential new target in AML treatment strategies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Detection of high frequency of MAD20 allelic variants of Plasmodium falciparum merozoite surface protein 1 gene from Adama and its surroundings, Oromia, Ethiopia

Background One of the major challenges in developing an effective vaccine against asexual stages of Plasmodium falciparum is genetic polymorphism within parasite population. Understanding the genetic polymorphism like block 2 region of merozoite surface protein-1 (msp-1) gene of P. falciparum enlighten mechanisms underlining disease pathology, identification of the parasite clone profile from the isolates, transmission intensity and potential deficiencies of the ongoing malaria control and elimination efforts in the locality. Detailed understanding of local genetic polymorphism is an input to pave the way for better management, control and elimination of malaria. The aim of this study was to detect the most frequent allelic variant of the msp-1 gene of P. falciparum clinical isolates from selected health facilities in Adama town and its surroundings, Oromia, Ethiopia. Methods One hundred thirty-nine clinical isolates were successfully amplified for msp-1 gene using specific primers. Nested PCR amplification was conducted targeting K1, MAD20, and R033 alleles followed by gel electrophoresis for fragment analysis. Based on the detection of a PCR fragment, infections were classified as monoclonal or multiple infections. Results 19 different size polymorphism of msp-1 gene were identified in the study, with 67(48%) MAD20, 18 (13%) K-1 and 18 (13%) RO33 allelic family. Whereas, the multiple infections were 21(15%), 8 (5.8%), 4(2.9%), 3(2.2%) for MAD20 + K-1, MAD20 + RO33, K-1 + RO33, and MAD20 + K-1, RO33, respectively. The overall Multiplicity of infection (MOI) was 1.3 and the expected heterozygosity (He) was 0.39 indicating slightly low falciparum malaria transmission. Conclusion The status of msp-1 allele size polymorphism, MOI and He observed in the study revealed the presence of slightly low genetic diversity of P. falciparum clinical isolates. However, highly frequent MAD20 allelic variant was detected from clinical isolates in the study area. Moreover, the driving force that led to high predominance of MAD20 allelic variant revealed in such malaria declining region demands further research.

A universal vaccine candidate against Plasmodium vivax malaria confers protective immunity against the three PvCSP alleles

Malaria is a highly prevalent parasitic disease in regions with tropical and subtropical climates worldwide. Among the species of Plasmodium causing human malaria, P. vivax is the second most prevalent and the most geographically widespread species. A major target of a pre-erythrocytic vaccine is the P. vivax circumsporozoite protein (PvCSP). In previous studies, we fused two recombinant proteins representing three allelic variants of PvCSP (VK210, VK247 and P. vivax-like) to the mumps virus nucleocapsid protein to enhance immune responses against PvCSP. The objective of the present study was to evaluate the protective efficacy of these recombinants in mice challenged with transgenic P. berghei parasites expressing PvCSP allelic variants. Formulations containing Poly (I:C) or Montanide ISA720 as adjuvants elicited high and long-lasting IgG antibody titers specific to each PvCSP allelic variant. Immunized mice were challenged with two existing chimeric P. berghei parasite lines expressing PvCSP-VK210 and PvCSP-VK247. We also developed a novel chimeric line expressing the third allelic variant, PvCSP-P. vivax-like, as a new murine immunization-challenge model. Our formulations conferred partial protection (significant delay in the time to reach 1% parasitemia) against challenge with the three chimeric parasites. Our results provide insights into the development of a vaccine targeting multiple strains of P. vivax.

MicroRNAs as novel biomarkers for rivaroxaban therapeutic drug monitoring

Objectives The aim of this study is to assess micro-RNAs miR-142 and miR-39 as potential biomarkers for drug-monitoring of rivaroxaban among elderly patients with atrial fibrillation. Methods The study involved 57 patients with median (ME) age 87 years [80–94 years old] with nonvalvular atrial fibrillation admitted to a multidisciplinary hospital in Moscow. High-performance liquid chromatography with mass-spectrometry detection (HPLC-MS) was carried out to measure rivaroxaban concentrations. Carriership of CYP3A4 and ABCB1 was detected. MiRNA expression levels were measured. The activity of CYP3A4 isoenzyme was measured as the ratio of the concentrations of 6β-hydroxycortisol and cortisol. Results The miR-142 expression levels of patients with CC allelic variant polymorphism ABCB1 3435 C>T (rs1045642) were significantly higher compared to CT and TT variants 31.69 ± 1.60 vs. 34.06 ± 1.66 vs. 33.16 ± 1.77 (p=0.021). Carriers of TT allelic variant polymorphism ABCB1 rs4148738 had a higher concentration of the 6-beta-hydroxycortisol in urine compared to CC and CT variants 3,467.35 ± 1,055.53 vs. 3,453.52 ± 1,516.89 vs. 2,593.30 ± 1,172.52 (p=0.029). As for CYP3A4*22, the carriers of CC allelic variant had higher prothrombin time 14.10 ± 2.17 vs. 11.87 ± 0.60 and INR 1.31 ± 0.20 vs. 1.1 ± 0.06 but lower Quick’s value 74.52 ± 16.84 vs. 97.55 ± 10.54 (p=0.059). A positive correlation between the Ct miR-142 and the aPTT p=0.019 was noted. Also miR-142 has a correlation with Quick’s value p=0.095. There is no statistically significant connection between miR-142 and miR-39 expression levels and the plasma concentration of rivaroxaban (b coefficient=−2.055, SE 3.952, p=0.605 and b coefficient=1.546, SE 9.887, p=0.876 in the linear regression model respectively). Conclusions This study has assessed new potential biomarkers for rivaroxaban therapeutic drug monitoring: miR-142 and miR-39.

Detection of High Frequency of MAD20 Allelic Variants of Plasmodium Falciparum Merozoite Surface Protein 1 Gene from Adama and its Surroundings, Oromia, Ethiopia

Background: One of the major challenges in developing an effective vaccine against asexual stages of Plasmodium falciparum is genetic polymorphism within parasite population. Understanding the genetic polymorphism like block 2 region of merozoite surface protein (msp-1) genes of P. falciparum enlighten mechanisms underlining disease pathology, identification of the parasite clone profile from the isolates, transmission intensity and potential deficiencies of the ongoing malaria control and elimination effort in the locality. Detailed understanding of local genetic polymorphism is an input to pave the way for better management, control and elimination of malaria. The aim of this study was to detect the most frequent allelic variant of the merozoite surface protein (msp-1) gene of P. falciparum clinical isolates from selected health facilities in Adama town and its surroundings, Oromia, Ethiopia.Methods: A total of 139 clinical isolates were successfully amplified for msp-1 gene using specific sets of primer. Nested PCR amplification conducted, using specific primers targeting K1, MAD20, and R033 alleles followed by gel electrophoresis for fragment analysis. Based on the detection of a PCR fragment, infections were classified as monoclonal or multiple infections.Result: 19 different size polymorphism of msp-1 gene were identified in the study, with 67(48 %) MAD20, 18 (13 %) K-1 and 18 (13 %) RO33 allelic family. Whereas, the multiple infections were 21(15 %), 8(5.8 %), 4(2.9 %), 3(2.2 %) for MAD20+K-1, MAD20+RO33, K-1+ RO33, and MAD20+K-1, RO33, respectively. The overall Multiplicity of Infection (MOI) was 1.3 and the expected heterozygosity (He) was 0.58 indicating intermediate falciparum malaria transmission.Conclusion: The status of msp-1 allele size polymorphism, MOI and He observed in the study revealed an intermediate genetic diversity of P. falciparum clinical isolates, indicating that the ongoing malaria control and elimination effort should be intensified to effectively monitor the potential malaria resurgence in the study area. Moreover, deriving force that led to high predominance of MAD20 allelic variant revealed in such malaria declining region demands further research.