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Fulltext Comprehensive genomic and immunological characterization of Chinese non-small cell lung cancer patients

Zhang XC, Wang J, Shao GG, Wang Q, Qu X, Wang B, et al.

Nat Commun, 2019 04 16;10(1):1772.
PMID: 30992440 DOI: 10.1038/s41467-019-09762-1

Deep understanding of the genomic and immunological differences between Chinese and Western lung cancer patients is of great importance for target therapy selection and development for Chinese patients. Here we report an extensive molecular and immune profiling study of 245 Chinese patients with non-small cell lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures is found to be significantly higher in adenocarcinoma (ADC, 72.5%) compared with squamous cell carcinoma (SQCC, 54.4%). The correlation of genomic alterations with immune signatures reveals that low immune infiltration was associated with EGFR mutations in ADC samples, PI3K and/or WNT pathway activation in SQCC. While KRAS mutations are found to be significantly associated with T cell infiltration in ADC samples. The SQCC patients with high antigen presentation machinery and cytotoxic T cell signature scores are found to have a prolonged overall survival time.

Matched MeSH terms: Mutation
Fulltext Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis

Liam CK, Ahmad AR, Hsia TC, Zhou J, Kim DW, Soo RA, et al.

Clin Cancer Res, 2023 May 15;29(10):1879-1886.
PMID: 36971777 DOI: 10.1158/1078-0432.CCR-22-3318

PURPOSE: The final analyses of the INSIGHT phase II study evaluating tepotinib (a selective MET inhibitor) plus gefitinib versus chemotherapy in patients with MET-altered EGFR-mutant NSCLC (data cut-off: September 3, 2021).
PATIENTS AND METHODS: Adults with advanced/metastatic EGFR-mutant NSCLC, acquired resistance to first-/second-generation EGFR inhibitors, and MET gene copy number (GCN) ≥5, MET:CEP7 ≥2, or MET IHC 2+/3+ were randomized to tepotinib 500 mg (450 mg active moiety) plus gefitinib 250 mg once daily, or chemotherapy. Primary endpoint was investigator-assessed progression-free survival (PFS). MET-amplified subgroup analysis was preplanned.
RESULTS: Overall (N = 55), median PFS was 4.9 months versus 4.4 months [stratified HR, 0.67; 90% CI, 0.35-1.28] with tepotinib plus gefitinib versus chemotherapy. In 19 patients with MET amplification (median age 60.4 years; 68.4% never-smokers; median GCN 8.8; median MET/CEP7 2.8; 89.5% with MET IHC 3+), tepotinib plus gefitinib improved PFS (HR, 0.13; 90% CI, 0.04-0.43) and overall survival (OS; HR, 0.10; 90% CI, 0.02-0.36) versus chemotherapy. Objective response rate was 66.7% with tepotinib plus gefitinib versus 42.9% with chemotherapy; median duration of response was 19.9 months versus 2.8 months. Median duration of tepotinib plus gefitinib was 11.3 months (range, 1.1-56.5), with treatment >1 year in six (50.0%) and >4 years in three patients (25.0%). Seven patients (58.3%) had treatment-related grade ≥3 adverse events with tepotinib plus gefitinib and five (71.4%) had chemotherapy.
CONCLUSIONS: Final analysis of INSIGHT suggests improved PFS and OS with tepotinib plus gefitinib versus chemotherapy in a subgroup of patients with MET-amplified EGFR-mutant NSCLC, after progression on EGFR inhibitors.

Matched MeSH terms: Mutation
Fulltext Changes in the Carbon Metabolism of Escherichia coli During the Evolution of Doxycycline Resistance

Yang Y, Mi J, Liang J, Liao X, Ma B, Zou Y, et al.

Front Microbiol, 2019;10:2506.
PMID: 31736928 DOI: 10.3389/fmicb.2019.02506

Despite our continuous improvement in understanding the evolution of antibiotic resistance, the changes in the carbon metabolism during the evolution of antibiotic resistance remains unclear. To investigate the evolution of antibiotic resistance and the changes in carbon metabolism under antibiotic pressure, Escherichia coli K-12 was evolved for 38 passages under a concentration gradient of doxycycline (DOX). The 0th-passage sensitive strain W0, the 20th-passage moderately resistant strain M20, and the 38th-passage highly resistant strain E38 were selected for the determination of biofilm formation, colony area, and carbon metabolism levels, as well as genome and transcriptome sequencing. The MIC of DOX with E. coli significantly increased from 4 to 96 μg/ml, and the IC50 increased from 2.18 ± 0.08 to 64.79 ± 0.75 μg/ml after 38 passages of domestication. Compared with the sensitive strain W0, the biofilm formation amount of the resistant strains M20 and E38 was significantly increased (p < 0.05). Single-nucleotide polymorphisms (SNPs) were distributed in antibiotic resistance-related genes such as ribosome targets, cell membranes, and multiple efflux pumps. In addition, there were no mutated genes related to carbon metabolism. However, the genes involved in the biosynthesis of secondary metabolites and carbon metabolism pathway were downregulated, showing a significant decrease in the metabolic intensity of 23 carbon sources (p < 0.05). The results presented here show that there may be a correlation between the evolution of E. coli DOX resistance and the decrease of carbon metabolism, and the mechanism was worthy of further research, providing a theoretical basis for the prevention and control of microbial resistance.

Matched MeSH terms: Mutation
Fulltext Three cases of permanent neonatal diabetes mellitus: genotypes and management outcome

Ooi HL, Wu LL

Singapore Med J, 2012 Jul;53(7):e142-4.
PMID: 22815030

Neonatal diabetes mellitus (DM) is defined as insulin-requiring DM in the first six months of life. Unlike type 1 DM, it is a monogenic disorder resulting from a de novo mutation in the genes involved in the development of the pancreas, β-cell mass or secretory function. The majority of neonatal DM cases are caused by a heterozygous activating mutation in the KCNJ11 or ABCC8 genes that encode the Kir6.2 and SUR1 protein subunits, respectively, in the KATP channel. Sulphonylurea, a KATP channel inhibitor, can restore insulin secretion, hence offering an attractive alternative to insulin therapy. We report three cases of neonatal DM and their genetic mutations. Two patients were successfully switched over to sulphonylurea monotherapy with resultant improvement in the quality of life and a more stable blood glucose profile. Patients with neonatal DM should undergo genetic evaluation. For patients with KCNJ11 and ABCC8 gene mutation, oral sulphonylurea should be considered.

Matched MeSH terms: Mutation*
Fulltext A Hybrid SSA and SMA with Mutation Opposition-Based Learning for Constrained Engineering Problems

Wang S, Liu Q, Liu Y, Jia H, Abualigah L, Zheng R, et al.

Comput Intell Neurosci, 2021;2021:6379469.
PMID: 34531910 DOI: 10.1155/2021/6379469

Based on Salp Swarm Algorithm (SSA) and Slime Mould Algorithm (SMA), a novel hybrid optimization algorithm, named Hybrid Slime Mould Salp Swarm Algorithm (HSMSSA), is proposed to solve constrained engineering problems. SSA can obtain good results in solving some optimization problems. However, it is easy to suffer from local minima and lower density of population. SMA specializes in global exploration and good robustness, but its convergence rate is too slow to find satisfactory solutions efficiently. Thus, in this paper, considering the characteristics and advantages of both the above optimization algorithms, SMA is integrated into the leader position updating equations of SSA, which can share helpful information so that the proposed algorithm can utilize these two algorithms' advantages to enhance global optimization performance. Furthermore, Levy flight is utilized to enhance the exploration ability. It is worth noting that a novel strategy called mutation opposition-based learning is proposed to enhance the performance of the hybrid optimization algorithm on premature convergence avoidance, balance between exploration and exploitation phases, and finding satisfactory global optimum. To evaluate the efficiency of the proposed algorithm, HSMSSA is applied to 23 different benchmark functions of the unimodal and multimodal types. Additionally, five classical constrained engineering problems are utilized to evaluate the proposed technique's practicable abilities. The simulation results show that the HSMSSA method is more competitive and presents more engineering effectiveness for real-world constrained problems than SMA, SSA, and other comparative algorithms. In the end, we also provide some potential areas for future studies such as feature selection and multilevel threshold image segmentation.

Matched MeSH terms: Mutation
Recessive distal renal tubular acidosis in Sarawak caused by AE1 mutations

Choo KE, Nicoli TK, Bruce LJ, Tanner MJ, Ruiz-Linares A, Wrong OM

Pediatr Nephrol, 2006 Feb;21(2):212-7.
PMID: 16252102

Mutations of the AE1 (SLC4A1, Anion-Exchanger 1) gene that codes for band 3, the renal and red cell anion exchanger, are responsible for many cases of familial distal renal tubular acidosis (dRTA). In Southeast Asia this disease is usually recessive, caused either by homozygosity of a single AE1 mutation or by compound heterozygosity of two different AE1 mutations. We describe two unrelated boys in Sarawak with dRTA associated with compound heterozygosity of AE1 mutations. Both had Southeast Asian ovalocytosis (SAO), a morphological abnormality of red cells caused by a deletion of band 3 residues 400-408. In addition, one boy had a DNA sequence abnormality of band 3 residue (G701D), which has been reported from elsewhere in Southeast Asia. The other boy had the novel sequence abnormality of band 3 (Q759H) and profound hemolytic anemia.

Matched MeSH terms: Mutation*
Fulltext Tropical distal renal tubular acidosis: clinical and epidemiological studies in 78 patients

Khositseth S, Bruce LJ, Walsh SB, Bawazir WM, Ogle GD, Unwin RJ, et al.

QJM, 2012 Sep;105(9):861-77.
PMID: 22919024 DOI: 10.1093/qjmed/hcs139

Distal renal tubular acidosis (dRTA) caused by mutations of the SLC4A1 gene encoding the erythroid and kidney isoforms of anion exchanger 1 (AE1 or band 3) has a high prevalence in some tropical countries, particularly Thailand, Malaysia, the Philippines and Papua New Guinea (PNG). Here the disease is almost invariably recessive and can result from either homozygous or compound heterozygous SLC4A1 mutations.

Matched MeSH terms: Mutation/genetics*
3-Methylglutaconic aciduria, a frequent but underrecognized finding in carbamoyl phosphate synthetase I deficiency

Rokicki D, Pajdowska M, Trubicka J, Thong MK, Ciara E, Piekutowska-Abramczuk D, et al.

Clin Chim Acta, 2017 Aug;471:95-100.
PMID: 28526534 DOI: 10.1016/j.cca.2017.05.023

The urea cycle disorder carbamoyl phosphate synthetase I deficiency is an important differential diagnosis in the encephalopathic neonate. This intoxication type inborn error of metabolism often leads to neonatal death or severe and irreversible damage of the central nervous system, even despite appropriate treatment. Timely diagnosis is crucial, but can be difficult on routine metabolite level. Here, we report ten neonates from eight families (finally) diagnosed with CPS1 deficiency at three tertiary metabolic centres. In seven of them the laboratory findings were dominated by significantly elevated urinary 3-methylglutaconic acid levels which complicated the diagnostic process. Our findings are both important for the differential diagnosis of patients with urea cycle disorders and also broaden the differential diagnosis of hyperammonemia associated with 3-methylglutaconic aciduria, which was earlier only reported in TMEM70 and SERAC1 defect.

Matched MeSH terms: Mutation
Fulltext Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases

Maas RR, Iwanicka-Pronicka K, Kalkan Ucar S, Alhaddad B, AlSayed M, Al-Owain MA, et al.

Ann Neurol, 2017 Dec;82(6):1004-1015.
PMID: 29205472 DOI: 10.1002/ana.25110

OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1.
METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported.
RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills.
INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.

Matched MeSH terms: Mutation/genetics*
Fulltext Four products from Escherichia coli pseudogenes increase hydrogen production

Mohd Yusoff MZ, Hashiguchi Y, Maeda T, Wood TK

Biochem Biophys Res Commun, 2013 Oct 4;439(4):576-9.
PMID: 24025676 DOI: 10.1016/j.bbrc.2013.09.016

Pseudogenes are considered to be nonfunctional genes that lack a physiological role. By screening 3985 Escherichia coli mutants using chemochromic membranes, we found four pseudogenes involved in hydrogen metabolism. Knockouts of pseudogenes ydfW and ypdJ had a defective hydrogen phenotype on glucose and formate, respectively. Also, the knockout of pseudogene yqiG formed hydrogen from formate but not from glucose. For the yqiG mutant, 100% hydrogen recovery was obtained by the complementation of YqiG via a plasmid. The knockout of pseudogene ylcE showed hydrogen deficiency in minimal media which suggested that the role of YlcE is associated with cell growth. Hence, the products of these four pseudogenes play an important physiological role in hydrogen production in E. coli.

Matched MeSH terms: Mutation
Fulltext Lack of meaningful genotype-phenotype association in SCN1A-related infantile-onset epileptic encephalopathies

Siti Aishah Abdul Wahab, Yusnita Yakob, Khoo,Teik-Beng, Sangita Dharshini Terumalay, Vigneswari Ganesan, Teh,Chee-Ming, et al.

Neurology Asia, 2017;22(2):99-111.
MyJurnal

Background & Objective: SCN1A gene which encodes for sodium channel alpha 1 subunit has been
found to be the most common mutated gene in patients with epilepsy. This study aims to characterize the
SCN1A mutations as well as to describe genotype and phenotype association in children with SCN1Arelated
infantile-onset epileptic encephalopathies in Malaysia.

Methods: Children with infantile-onset
epileptic encephalopathy mostly suspected to have Dravet syndrome who had mutational analysis for
SCN1A gene from hospitals all over Malaysia were included in the study. Their epilepsy syndrome
diagnosis was classified into severe myoclonic epilepsy in infancy and its variants. Polymerase chain
reaction and bidirectional sequencing were used to identify SCN1A mutations.

Results: A total of 38
children with heterozygous mutations were analysed, 22 (57.9%) of which were novel mutations.
Truncated mutations were the most common mutation type (19, 50%). Other mutation types were
missense mutations (14, 36.8%), splice site mutations (4, 10.5%) and in-frame deletion (1, 2.6%). The
mean age of seizure onset was 4.7 months. Seizure following vaccination was observed in 26.3% of
the children. All of them had drug resistant epilepsy. There was no significant association between
the type of mutation with the syndromic diagnosis, age of seizure onset, tendency of the seizures to
cluster or having status epilepticus, mean age when developmental delay was observed and response
to various antiepileptic drugs.

Conclusion: This study expands the spectrum of SCN1A mutations and proves the importance of
SCN1A gene testing in diagnosing infantile-onset epileptic encephalopathies patients. Although, our
study does not support any clinically meaningful genotype-phenotype association for SCN1A-related
infantile-onset epileptic encephalopathies, the clinical characteristics of our cohort are similar to those
that have been described in previous studies.

Matched MeSH terms: Mutation, Missense
Fulltext Hb E beta +-thalassaemia in west Malaysia: clinical features in the most common beta-thalassaemia mutation of the Malays [IVS 1-5 (G-->C)]

George E, Wong HB

Singapore Med J, 1993 Dec;34(6):500-3.
PMID: 8153710

Patients with the Hb beta + [IVS 1-5 (G-->C)] clinically presented as beta-thalassaemia intermedia and remained asymptomatic in the absence of blood transfusions. With or without blood transfusions the patients were short and had moderate to marked thalassaemia facies. Children who received blood transfusions showed progressive iron loading with age. The serum ferritin and serum alanine transaminase levels were significantly raised in the patients who were given blood transfusions. In the presence of blood transfusions, and absence of adequate iron chelation therapy, splenectomy became an inevitable event at some stage of the disease because of increasing transfusing requirements.

Matched MeSH terms: Mutation/genetics
Fulltext Primary imatinib resistance in chronic myeloid leukemia patients in a developing country: BCR-ABL kinase domain mutations or BCR-ABL independent mechanisms?

Yap E, Tumian NR, Azma RZ, Sharifah NA, Salwati S, Hamidah NH, et al.

Malays J Pathol, 2017 Aug;39(2):107-113.
PMID: 28866691 MyJurnal

Clinical resistance to imatinib (IM) in chronic myeloid leukemia (CML) carries adverse consequences. We investigated 22 CML patients who developed IM-resistance for BCR-ABL kinase domain (KD) mutations. The median follow-up for this study was 101.9 months (range: 22.2 to 176.5 months) and the estimated mean overall survival was 150.87 months (95% CI: 130.0 to 171.0). Five out of 22 patients tested positive for BCR-ABL KD mutations: 2 had T315I, 2 had E255K and 1 had V289F mutations. Of the remaining 17 patients who did not harbor BCR-ABL KD mutations, 11 patients received nilotinib while the rest continued on IM. All 17 achieved haematological remission but only 5 patients achieved complete cytogenetic remission, 4 of whom did so after switching to nilotinib. Our study shows that most of our IM-resistant patients do not test positive for BCR-ABL KD mutations by available testing methods and the role of second generation tyrosine kinase inhibitors remains undetermined. A critical analysis of the BCR-ABL KD mutations and the underlying mechanisms/ pathways of BCR-ABL independent IM-resistance along with potential treatments in the horizon will be discussed.

Matched MeSH terms: Mutation
Fulltext Novel defect in phosphatidylinositol 4-kinase type 2-alpha (PI4K2A) at the membrane-enzyme interface is associated with metabolic cutis laxa

Mohamed M, Gardeitchik T, Balasubramaniam S, Guerrero-Castillo S, Dalloyaux D, van Kraaij S, et al.

J Inherit Metab Dis, 2020 11;43(6):1382-1391.
PMID: 32418222 DOI: 10.1002/jimd.12255

Inherited cutis laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several cutis laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with cutis laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4-kinase type IIα, caused by a homozygous missense mutation in the PI4K2A gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4-phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl-chain pools of PI4P and PI(4,5)P2 were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4-kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P2 and PI(3,4,5)P3 . Although neurologic involvement is common, cutis laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation in PI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.

Matched MeSH terms: Mutation, Missense*
Fulltext Flexible model-based clustering of mixed binary and continuous data: application to genetic regulation and cancer

Zainul Abidin FN, Westhead DR

Nucleic Acids Res, 2017 04 20;45(7):e53.
PMID: 27994031 DOI: 10.1093/nar/gkw1270

Clustering is used widely in 'omics' studies and is often tackled with standard methods, e.g. hierarchical clustering. However, the increasing need for integration of multiple data sets leads to a requirement for clustering methods applicable to mixed data types, where the straightforward application of standard methods is not necessarily the best approach. A particularly common problem involves clustering entities characterized by a mixture of binary data (e.g. presence/absence of mutations, binding, motifs and epigenetic marks) and continuous data (e.g. gene expression, protein abundance, metabolite levels). Here, we present a generic method based on a probabilistic model for clustering this type of data, and illustrate its application to genetic regulation and the clustering of cancer samples. We show that the resulting clusters lead to useful hypotheses: in the case of genetic regulation these concern regulation of groups of genes by specific sets of transcription factors and in the case of cancer samples combinations of gene mutations are related to patterns of gene expression. The clusters have potential mechanistic significance and in the latter case are significantly linked to survival. The method is available as a stand-alone software package (GNU General Public Licence) from http://github.com/BioToolsLeeds/FlexiCoClusteringPackage.git.

Matched MeSH terms: Mutation
Fulltext Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study

Khan A, Hussain S, Ahmad S, Suleman M, Bukhari I, Khan T, et al.

Comput Biol Med, 2022 02;141:105163.
PMID: 34979405 DOI: 10.1016/j.compbiomed.2021.105163

The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' interaction networks by graph kernels along with evolutionary, network metrics, and energetic information. Our analysis revealed that N501I, N501T, and N501V increase the binding affinity and alter the intra and inter-residue bonding networks. The N501T has shown strong positive selection and fitness in other animals. Docking results and repeated simulations (three times) confirmed the structural stability and tighter binding of these three variants, correlated with the previous results following the global stability trend. Consequently, we reported three variants N501I, N501T, and N501V could worsen the situation further if they emerged. The relations between the viral fitness and binding affinity is a complicated game thus the emergence of high affinity mutations in the SARS-CoV-2 RBD brings up the question of whether or not positive selection favours these mutations or not?

Matched MeSH terms: Mutation
Fulltext Biochemical and molecular characteristics of Malaysian patients with lysinuric protein intolerance

Habib A, Azize NA, Yakob Y, Md Yunus Z, Wee TK

Malays J Pathol, 2016 Dec;38(3):305-310.
PMID: 28028301 MyJurnal

Lysinuric protein intolerance (LPI) is an inborn error of dibasic amino acid transport due to a defect in the dibasic amino acid transporter in the renal and intestine and has a heterogenous presentation. Three Malaysian patients with LPI were studied and their biochemical and molecular findings compared. There were differences and similarities in the biochemical and molecular findings. Molecular analysis of SLC7A7 gene revealed a novel mutation c.235G>A; p.(Gly79Arg) in exon three in Patient 1 and a mutation c.1417C>T; p.(Arg473*) in exon 10 in patient 2 and 3. The degree of concentration of dibasic amino acids may determine the type of disease of the cell membrane transport, however, a positive molecular confirmation will secure the diagnosis.

Matched MeSH terms: DNA Mutational Analysis; Mutation
The brave new world of genetic testing in the management of the dyslipidaemias

Nawawi HM, Chua YA, Watts GF

Curr Opin Cardiol, 2020 05;35(3):226-233.
PMID: 32097179 DOI: 10.1097/HCO.0000000000000721

PURPOSE OF REVIEW: With the exception of familial hypercholesterolaemia, the value of genetic testing for managing dyslipidaemias is not established. We review the genetics of major dyslipidaemias in context of clinical practice.
RECENT FINDINGS: Genetic testing for familial hypercholesterolaemia is valuable to enhance diagnostic precision, cascade testing, risk prediction and the use of new medications. Hypertriglyceridaemia may be caused by rare recessive monogenic, or by polygenic, gene variants; genetic testing may be useful in the former, for which antisense therapy targeting apoC-III has been approved. Familial high-density lipoprotein deficiency is caused by specific genetic mutations, but there is no effective therapy. Familial combined hyperlipidaemia (FCHL) is caused by polygenic variants for which there is no specific gene testing panel. Familial dysbetalipoproteinaemia is less frequent and commonly caused by APOE ε2ε2 homozygosity; as with FCHL, it is responsive to lifestyle modifications and statins or/and fibrates. Elevated lipoprotein(a) is a quantitative genetic trait whose value in risk prediction over-rides genetic testing; treatment relies on RNA therapeutics.
SUMMARY: Genetic testing is not at present commonly available for managing dyslipidaemias. Rapidly advancing technology may presage wider use, but its worth will require demonstration of cost-effectiveness and a healthcare workforce trained in genomic medicine.

Matched MeSH terms: Mutation
Fulltext HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block

Nor Rashid N, Yong ZL, Yusof R, Watson RJ

Virol J, 2016 Jan 04;13:2.
PMID: 26728921 DOI: 10.1186/s12985-015-0460-8

Retinoblastoma like protein 2 (RBL2) or p130 is a member of the pocket protein family, which is infrequently mutated in human tumours. Its expression is posttranscriptionally regulated and largely G0 restricted. We have previously shown that E6/E7 oncoproteins encoded by human papillomavirus (HPV) type 16, which is a high-risk type for cervical cancer development, must target p130 to promote the host cell to exit from quiescence (G0) state and enter S phase of the cell cycle. P130 is associated with the DREAM (DP, RB-like, E2F and MuvB) complex in G0/G1, which prevents S phase progression by repressing transcription of E2F-regulated genes. E7 proteins could potentially disrupt the p130-DREAM complex through two known mechanisms: direct interaction with p130 or induction of cyclin dependent kinase 2 (CDK2) phosphorylation by interacting with its inhibitor, p21(CIP1).

Matched MeSH terms: Mutation
Synthesis of conjugated linoleic acid-rich triacylglycerols by immobilized mutant lipase with excellent capability and recyclability

Lian W, Li D, Zhang L, Wang W, Faiza M, Tan CP, et al.

Enzyme Microb Technol, 2018 Oct;117:56-63.
PMID: 30037552 DOI: 10.1016/j.enzmictec.2018.06.007

Conjugated linoleic acid (CLA)-rich triacylglycerols (TAG) have received significant attention owing to their health promoting properties. In this study, CLA-rich TAG were successfully synthesized by an immobilized mutant lipase (MAS1-H108A)-catalyzed esterification of CLA-rich fatty acids and glycerol under vacuum. MAS1-H108A was first immobilized onto ECR1030 resin. Results showed that the lipase/support ratio of 41 mg/g was suitable for the immobilization and the thermostability of immobilized MAS1-H108A was greatly enhanced. Subsequently, the immobilized MAS1-H108A was employed for the synthesis of CLA-rich TAG and 95.21% TAG with 69.19% CLA was obtained under the optimized conditions. The TAG content (95.21%) obtained by immobilized MAS1-H108A is the reported highest value thus far, which was significantly higher than that (9.26%) obtained by Novozym 435 under the same conditions. Although the TAG content comparable to the results obtained in this study could also be obtained by Novozym 435, the used enzyme amount is approximately 5-fold of the immobilized MAS1-H108A. Additionally, the immobilized MAS1-H108A exhibited excellent recyclability during esterification retaining 95.11% of its initial activity after 10 batches. Overall, such immobilized mutant lipase with superior esterification activity and recyclability has the potential to be used in oils and fats industry.

Matched MeSH terms: Mutation*

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