Articles Related to mutations
Prevalence of Minority Mutations That Confer Multi-Drug Resistance Among Patients Failing a Nucleoside Reverse Transcriptase Inhibitor Based Regimen in Uganda
Background:The extensive use of antiretroviral therapy has favored the emergence of multiple patterns of drug resistance mutations. These mutations evolve over time and are only detected by the conventional Sanger sequencing technology when they exceed 20% at which time there may be cross resistance. Unfortunately, the controversy surrounding the significance of these minority drug resistance mutations is still overwhelming.
Methods: Samples were obtained from patients who were failing on an NRTI based regimen between 2010 and 2019. For the subtype A and D analysis, 1000 patient samples were analyzed while the subtype C sub-analysis was comprised of 363 samples. Sanger based sequencing was performed as part of the standard of care. A subset of these samples was further analyzed using the Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cut off to determine the prevalence of minority multi-drug resistant variants.
Results: Although Thymidine analog mutations (TAMs) were prevalent in all subtypes, our analyses showed that these mutations occurred in significantly less proportions among subtype C infections when compared with the subtype A and D counterparts. On the other hand, the Q151M mutation complex was significantly more predominant among patients harboring subtype C variants. Analysis using NGS revealed that minority drug resistant mutations that confer multi-drug resistance (MDR) were present even in patients who exhibited a susceptible genotype based on the Sanger sequencing technique.
Conclusion: Although HIV-1 MDR variants occur in all subtypes, their predominance is subtype specific with TAMs being significantly more predominant among subtype A and D while the Q151M complex more predominant among patients harboring subtype C viruses. Even in patients with a fully susceptible genotype based on Sanger technology, minority variants are present and their evolution to full blown MDR occurs over time such that if their early detection is missed, cross resistance is inevitable.
Correlation of Hemostatic Parameters with Poly (ADP-ribose) Polymerase-1 (PARP-1) Polymorphisms, Mutations, Laboratory, and Clinical Characteristics in 114 Patients with Philadelphia-Negative Myeloproliferative Neoplasms
Patients with Philadelphia-negative myeloproliferative neoplasms (PN-MPN) are at a higher risk for venous thrombosis. Thromboelastometry may prove efficient to evaluate the patient’s thrombotic risk. In this study, based on data from
114 patients with PN-MPN from a single center in Greece, hemostatic profile was assessed with routine coagulation
tests, Rotational Thromboelastometry (ROTEM®
), and Platelet Function Analyzer (PFA)-100 and correlated with clinical,
laboratory, treatment characteristics, gene mutations and polymorphisms of poly (ADP-ribose) polymerase-1 (PARP-1)
Prevalence and Genetic Profile of β-Thalassemia Associated Mutations in a Mauritanian Population
Although common in the Mediterranean populations, β-thalassemia are present in various other parts of the world including
south Asia and Africa. This study was aimed to re-evaluate the prevalence of β thalassemia, the specific underlying β globin gene
mutations and their associated haplotypes in the Mauritanian population.
An Insight into the Role of Spliceosomal Mutations in Myelodysplastic Syndromes
The identification of altered splicing signatures in Myelodysplastic Syndromes (MDS) could likely provide key markers for diagnosis, prognostication and development of novel therapeutics. This review presents an insight into role of spliceosomal gene mutations in the pathogenesis of MDS, emphasizing on their clinical and prognostic significance. We also discuss emerging studies delineating the functional consequences of these mutations and pointing towards the emergence of a new leukemogenic pathway involving spliceosomal dysfunction.
Mechanisms of Resistance to Kinase Inhibitors and Strategies to Prevent the Development of Drug Resistance
Targeting mutant proteins and associated signaling pathways of driver oncogenes by small molecule kinase inhibitors (KIs) are a
promising strategy of cancer therapy. However, despite the initial success of treatment, KIs often become ineffective as intrinsic and
acquired resistance. This article reviews the English-language literature to explore the underlying mechanisms of drug resistance and
to present a challenge for developing drugs to overcome resistance. Mechanisms of acquired resistance include 1) the selection of
pre-existing subclones with other mutations, 2) the emergence of secondary mutations in the target kinase domain, 3) upregulation
of kinases both within the same kinase family and their related kinase families, as well as activation of alternative bypass pathways, 4)
epithelial-mesenchymal transition, 5) overexpression of pro-survival Bcl-2 family proteins and 6) drug efflux mechanisms. Currently
available methods are to obtain tumor biopsy samples at recurrence or progression if the tumor lesion is accessible to a biopsy and to
use the second- and third-generation KIs based on the individual need of each patient. Furthermore, recent computational challenges
provide design principles to prevent the development of drug resistance. In conclusion, we provide an overview of the postulated
resistance mechanisms and highlight the future direction of computational structure-based design of new potent KIs.
Pulmonary Adenocarcinoma Transforming into Small Cell Carcinoma: An Extreme Rarity
Primary small cell lung cancer (SCLC) showing epidermal growth factor receptor (EGFR) mutation is extremely rare. Transformation into SCLC has been reported as an evolution of lung adenocarcinoma acquiring resistance to EGFR tyrosine kinase inhibitors (TKI) and is considered to be a rare resistance mechanism of EGFR-TKI therapy.
Responses and Survival under Pegylated Interferon α2a Treatment for Patients with Post-MPN Acute Myeloid Leukemia and Acute Panmyelosis with Myelofibrosis
We report here for the first time the efficacy of pegylated interferon α2a (Peg-Ifn) as a therapy for patients with myelofibrosis and high blast counts. We treated four patients who were in an accelerated phase of myeloproliferative neoplasms or acute panmyelosis with myelofibrosis using only this drug.
Congenital Dyserythropoietic Anemia Type III and Primary Hemochromatosis; Coexistence of Mutations in KIF23 and HFE
Congenital dyserythropoietic anemia type III (CDA III) can be caused by mutation in KIF23. CDA III differs from CDA I and II in the sense that secondary hemochromatosis has not been reported. However, we have observed elevated serum ferritin in a CDA III family.
Immunodeficiency and Microbial Infections
Immunodeficiency refers to failure of immune system to encounter infections by different microbial pathogens such as fungi, bacteria, viruses and protozoan. This is called acquired or secondary immunodeficiency syndrome (SIS).
Study on Mitochondrial DNA Heteroplasmy from Liver, Kidney and Muscle of Common Carp
Mitochondrial DNA (mtDNA) heteroplasmy has been found to be commonly present in many organisms. However, the studies on the mitochondrial heteroplasmy within group of fishes are currently lacking. This specific purpose of this study was to investigate the mtDNA heteroplasmy in different organs within group of common carp.
Functional Protein Domains Evolve Very Specifically Over Mutations
Mutation in a single nucleotide of a gene has the potential to change the structure and/or function of its protein. Albeit simply saying, it is not observed to be a general phenomenon. The effect of mutation is primarily determined by the stereochemical nature of the amino acid which has replaced the previous amino acid, resulting in the residue location being affected. Here we show that despite a change in the frequency of occurrence of a particular amino acid in a particular protein in different types of organisms, the overall function of the protein can still remain unaffected, even when the resultant protein conformation is relatively altered.
Molecular Mechanisms of Mismatch Repair Genes in Cancer – A Brief Review
The DNA mismatch repair (MMR) system is necessary for the maintenance of genomic stability. The MMR system promotes genomic
fidelity by repairing base-base mismatches, insertion-deletion loops (IDLs) and heterologies generated during DNA replication and recombination.
Perspectives and Potential Applications of Ruthenium-Based Nanocarriers for Cancer Therapy
Cancer is a highly heterogeneous disease characterised by continuous uncontrolled growth and expansion of abnormal cells. In general, in tumor cells the signalling pathways regulating cellular processes, as cell growth and division and cell to cellcommunication result strongly altered.
Editorial Board Members Related to mutations
PATRICIA A. KRUK
Professor
Department of Obstetrics and Gynecology
USF Morsani College of Medicine
University of South Florida
United States
Department of Obstetrics and Gynecology
USF Morsani College of Medicine
University of South Florida
United States
SONAL GUPTA
Assistant Professor
Department of Pathology
University of Texas MD Anderson Cancer Center
United States
Department of Pathology
University of Texas MD Anderson Cancer Center
United States
Bassam R. Ali
Professor
Department of Pathology
College of Medicine and Health Sciences
UAE University
United Arab Emirates
Department of Pathology
College of Medicine and Health Sciences
UAE University
United Arab Emirates
Boris A. Reva
Associate Professor
Department of Genetics and Genomics Sciences
Icahn School of Medicine at Mount Sinai
United States
Department of Genetics and Genomics Sciences
Icahn School of Medicine at Mount Sinai
United States
