Rapamycin: one drug, many effects.
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC3972801 | biostudies-literature | 2014 Mar
REPOSITORIES: biostudies-literature
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Project description:Definition of preleukemia has evolved. It was first used to describe the myelodysplastic syndrome (MDS) with a propensity to progress to acute myeloid leukemia (AML). Individuals with germline mutations of either RUNX1, CEBPA, or GATA2 can also be called as preleukemic because they have a markedly increased incidence of evolution into AML. Also, alkylating chemotherapy or radiation can cause MDS/preleukemia, which nearly always progress to AML. More recently, investigators noted that AML patients who achieved complete morphological remission after chemotherapy often have clonal hematopoiesis predominantly marked by either DNMT3A, TET2 or IDH1/2 mutations, which were also present at diagnosis of AML. This preleukemic clone represents involvement of an early hematopoietic stem cells, which is resistant to standard therapy. The same clonal hematopoietic mutations have been identified in older 'normal' individuals who have a modest increased risk of developing frank AML. These individuals have occasionally been said, probably inappropriately, to have a preleukemia clone. Our evolving understanding of the term preleukemia has occurred by advancing technology including studies of X chromosome inactivation, cytogenetics and more recently deep nucleotide sequencing.
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Project description:Tau, a member of the microtubule-associated proteins, is a known component of the neuronal cytoskeleton; however, in the brain tissue, it is involved in other vital functions beyond maintaining the cellular architecture. The pathologic tau forms aggregates inside the neurons and ultimately forms the neurofibrillary tangles. Intracellular and extracellular accumulation of different tau isoforms, including dimers, oligomers, paired helical filaments and tangles, lead to a highly heterogenous group of diseases named "Tauopathies". About twenty-six different types of tauopathy diseases have been identified that have different clinical phenotypes or pathophysiological characteristics. Although all these diseases are identified by tau aggregation, they are distinguishable based on the specific tau isoforms, the affected cell types and the brain regions. The neuropathological and phenotypical heterogeneity of these diseases impose significant challenges for discovering new diagnostic and therapeutic strategies. Here, we review the recent literature on tau protein and the pathophysiological mechanisms of tauopathies. This article mainly focuses on physiologic and pathologic tau and aims to summarize the upstream and downstream events and discuss the current diagnostic approaches and therapeutic strategies.
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Project description: Not available
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Project description:OBJECTIVE:Lung cancer is classified as a single entity comprised of multiple histological subtypes. But how similar are these subtypes on a genetic level? This paper aims to address this question through a concise overview of germline and somatic differences between small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma. METHODS:We reveal the weak overlap found between these 3 lung cancer subtypes using published data from one of the largest germline genetic studies on lung cancer to date and somatic mutation data from Catalogue of Somatic Mutations in Cancer (COSMIC). RESULTS:These data indicate that these 3 subtypes share very little with each other at the genetic level. At the germline SNP level, only 24 independent SNPs from 2 chromosomes were shared across all 3 subtypes. We also demonstrate that only 30 unique cancer-specific mutations overlap the 3 subtypes from COSMIC, and that this is fewer than overlapping mutations chosen at random. Finally, we show that only 3 somatic mutational signatures are shared between these 3 subtypes. CONCLUSION:This paper highlights that these 3 lung cancer subtypes may be distinct diseases at the genetic level. In the era of precision medicine, we feel that these genomic differences will be of utmost importance in the choice of lung cancer therapy in the future.
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Project description:ST-segment elevation in patients sedated with propofol may be a sign of imminent malignant arrhythmias. Although propofol infusion syndrome-electrocardiographic abnormalities are usually described as Brugada-pattern, in unique cases nearly ubiquitous and extensive J-point and ST-segment elevation may be observed. These patients should undergo an ajmaline test following recovery. (Level of Difficulty: Beginner.).
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Project description:The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction and accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, and progressive supranuclear palsy collectively impact millions of patients and their families worldwide. Despite years of drug development using a variety of mechanisms of action, no therapeutic directed against tau has been approved for clinical use. This raises important questions about our current model of tau pathology and invites thoughtful consideration of our approach to nonclinical models and clinical trial design. In this article, we review what is known about the biology and genetics of tau, placing it in the context of current and failed clinical trials. We highlight potential reasons for the lack of success to date and offer suggestions for new pathways in therapeutic development. Overall, our viewpoint to the future is optimistic for this important group of neurodegenerative diseases.
| S-EPMC10963923 | biostudies-literature
Project description:In the last decade, it has become evident that RNA is frequently found in DNA. It is now well established that single embedded ribonucleoside monophosphates (rNMPs) are primarily introduced by DNA polymerases and that longer stretches of RNA can anneal to DNA, generating RNA:DNA hybrids. Among them, the most studied are R-loops, peculiar three-stranded nucleic acid structures formed upon the re-hybridization of a transcript to its template DNA. In addition, polyribonucleotide chains are synthesized to allow DNA replication priming, double-strand breaks repair, and may as well result from the direct incorporation of consecutive rNMPs by DNA polymerases. The bright side of RNA into DNA is that it contributes to regulating different physiological functions. The dark side, however, is that persistent RNA compromises genome integrity and genome stability. For these reasons, the characterization of all these structures has been under growing investigation. In this review, we discussed the origin of single and multiple ribonucleotides in the genome and in the DNA of organelles, focusing on situations where the aberrant processing of RNA:DNA hybrids may result in multiple rNMPs embedded in DNA. We concluded by providing an overview of the currently available strategies to study the presence of single and multiple ribonucleotides in DNA in vivo.
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Project description:SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. The genome of SARS-CoV-2 encodes nine accessory proteins that are involved in host-pathogen interaction. ORF8 is unique among these accessory proteins. SARS-CoV-2 ORF8 shares a surprisingly low amino acid sequence similarity with SARS-COV ORF8 (30%), and it is presumed to have originated from bat. Studies have shown that ORF8 exerts multiple different functions that interfere with host immune responses, including the downregulation of MHC class I molecules. These functions may represent strategies of host immune evasion. The x-ray crystal structure of ORF8 revealed an immunoglobulin-like domain with several distinguishing features. To date, there are numerous unanswered questions about SARS-CoV-2 ORF8 protein and its structure-function relationship that we discuss in this mini-review. A better understanding of how ORF8 interacts with components of the immune system is needed for elucidating COVID-19 pathogenesis and to develop new avenues for the treatment of the disease.
| S-EPMC9637571 | biostudies-literature
Project description:BackgroundIn the field of movement disorders, what you see (phenotype) is seldom what you get (genotype). Whereas 1 phenotype was previously associated to 1 gene, the advent of next-generation sequencing (NGS) has facilitated an exponential increase in disease-causing genes and genotype-phenotype correlations, and the "one-phenotype-many-genes" paradigm has become prominent.ObjectivesTo highlight the "one-phenotype-many-genes" paradigm by discussing the main challenges, perspectives on how to address them, and future directions.MethodsWe performed a scoping review of the various aspects involved in identifying the underlying molecular cause of a movement disorder phenotype.ResultsThe notable challenges are (1) the lack of gold standards, overlap in clinical spectrum of different movement disorders, and variability in the interpretation of classification systems; (2) selecting which patients benefit from genetic tests and the choice of genetic testing; (3) problems in the variant interpretation guidelines; (4) the filtering of variants associated with disease; and (5) the lack of standardized, complete, and up-to-date gene lists. Perspectives to address these include (1) deep phenotyping and genotype-phenotype integration, (2) adherence to phenotype-specific diagnostic algorithms, (3) implementation of current and complementary bioinformatic tools, (4) a clinical-molecular diagnosis through close collaboration between clinicians and genetic laboratories, and (5) ongoing curation of gene lists and periodic reanalysis of genetic sequencing data.ConclusionsDespite the rapidly emerging possibilities of NGS, there are still many steps to take to improve the genetic diagnostic yield. Future directions, including post-NGS phenotyping and cohort analyses enriched by genotype-phenotype integration and gene networks, ought to be pursued to accelerate identification of disease-causing genes and further improve our understanding of disease biology.
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