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Microbiome Jan 2023Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is thought to involve alterations in the gut microbiome, but robust microbial signatures have...
BACKGROUND
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is thought to involve alterations in the gut microbiome, but robust microbial signatures have been challenging to identify. As prior studies have primarily focused on composition, we hypothesized that multi-omics assessment of microbial function incorporating both metatranscriptomics and metabolomics would further delineate microbial profiles of IBS and its subtypes.
METHODS
Fecal samples were collected from a racially/ethnically diverse cohort of 495 subjects, including 318 IBS patients and 177 healthy controls, for analysis by 16S rRNA gene sequencing (n = 486), metatranscriptomics (n = 327), and untargeted metabolomics (n = 368). Differentially abundant microbes, predicted genes, transcripts, and metabolites in IBS were identified by multivariate models incorporating age, sex, race/ethnicity, BMI, diet, and HAD-Anxiety. Inter-omic functional relationships were assessed by transcript/gene ratios and microbial metabolic modeling. Differential features were used to construct random forests classifiers.
RESULTS
IBS was associated with global alterations in microbiome composition by 16S rRNA sequencing and metatranscriptomics, and in microbiome function by predicted metagenomics, metatranscriptomics, and metabolomics. After adjusting for age, sex, race/ethnicity, BMI, diet, and anxiety, IBS was associated with differential abundance of bacterial taxa such as Bacteroides dorei; metabolites including increased tyramine and decreased gentisate and hydrocinnamate; and transcripts related to fructooligosaccharide and polyol utilization. IBS further showed transcriptional upregulation of enzymes involved in fructose and glucan metabolism as well as the succinate pathway of carbohydrate fermentation. A multi-omics classifier for IBS had significantly higher accuracy (AUC 0.82) than classifiers using individual datasets. Diarrhea-predominant IBS (IBS-D) demonstrated shifts in the metatranscriptome and metabolome including increased bile acids, polyamines, succinate pathway intermediates (malate, fumarate), and transcripts involved in fructose, mannose, and polyol metabolism compared to constipation-predominant IBS (IBS-C). A classifier incorporating metabolites and gene-normalized transcripts differentiated IBS-D from IBS-C with high accuracy (AUC 0.86).
CONCLUSIONS
IBS is characterized by a multi-omics microbial signature indicating increased capacity to utilize fermentable carbohydrates-consistent with the clinical benefit of diets restricting this energy source-that also includes multiple previously unrecognized metabolites and metabolic pathways. These findings support the need for integrative assessment of microbial function to investigate the microbiome in IBS and identify novel microbiome-related therapeutic targets. Video Abstract.
Topics: Humans; Gastrointestinal Microbiome; Irritable Bowel Syndrome; Multiomics; RNA, Ribosomal, 16S; Feces; Habits
PubMed: 36624530
DOI: 10.1186/s40168-022-01450-5 -
Science Translational Medicine Jun 2023Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ()-mutant high-grade serous ovarian carcinoma (HGSC). However,...
Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ()-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant -mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with -mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase () and cyclin E1 () overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. reversion mutation in previously PARPi-treated -mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with -mutant HGSC.
Topics: Animals; Female; Humans; Mice; Antineoplastic Agents; Biomarkers; BRCA1 Protein; Breast Neoplasms; Drug Resistance, Neoplasm; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 37343085
DOI: 10.1126/scitranslmed.add7872 -
Pathogens (Basel, Switzerland) Mar 2023DNA repair defects are heterogenous conditions characterized by a wide spectrum of clinical phenotypes. The common presentations of DNA repair defects include increased... (Review)
Review
DNA repair defects are heterogenous conditions characterized by a wide spectrum of clinical phenotypes. The common presentations of DNA repair defects include increased risk of cancer, accelerated aging, and defects in the development of various organs and systems. The immune system can be affected in a subset of these disorders leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may occur due to primary defects in T, B, or NK cells and other factors such as anatomic defects, neurologic disorders, or during chemotherapy. Consequently, the characteristics of the infections may vary from mild upper respiratory tract infections to severe, opportunistic, and even fatal infections with bacteria, viruses, or fungi. Here, infections in 15 rare and sporadic DNA repair defects that are associated with immunodeficiencies are discussed. Because of the rarity of some of these conditions, limited information is available regarding infectious complications.
PubMed: 36986362
DOI: 10.3390/pathogens12030440 -
JMIR Dermatology Oct 2023Congenital telangiectatic erythema (CTE), also known as Bloom syndrome, is a rare autosomal recessive disorder characterized by below-average height, a narrow face, a... (Review)
Review
BACKGROUND
Congenital telangiectatic erythema (CTE), also known as Bloom syndrome, is a rare autosomal recessive disorder characterized by below-average height, a narrow face, a red skin rash occurring on sun-exposed areas of the body, and an increased risk of cancer. CTE is one of many genodermatoses and photodermatoses associated with defects in DNA repair. CTE is caused by a mutation occurring in the BLM gene, which causes abnormal breaks in chromosomes.
OBJECTIVE
We aimed to analyze the existing literature on CTE to provide additional insight into its heredity, the spectrum of clinical presentations, and the management of this disorder. In addition, the gaps in current research and the use of artificial intelligence to streamline clinical diagnosis and the management of CTE are outlined.
METHODS
A literature search was conducted on PubMed, DOAJ, and Scopus using search terms such as "congenital telangiectatic erythema," "bloom syndrome," and "bloom-torre-machacek." Due to limited current literature, studies published from January 2000 to January 2023 were considered for this review. A total of 49 sources from the literature were analyzed.
RESULTS
Through this scoping review, the researchers were able to identify several publications focusing on Bloom syndrome. Some common subject areas included the heredity of CTE, clinical presentations of CTE, and management of CTE. In addition, the literature on rare diseases shows the potential advancements in understanding and treatment with artificial intelligence. Future studies should address the causes of heterogeneity in presentation and examine potential therapeutic candidates for CTE and similarly presenting syndromes.
CONCLUSIONS
This review illuminated current advances in potential molecular targets or causative pathways in the development of CTE as well as clinical features including erythema, increased cancer risk, and growth abnormalities. Future studies should continue to explore innovations in this space, especially in regard to the use of artificial intelligence, including machine learning and deep learning, for the diagnosis and clinical management of rare diseases such as CTE.
PubMed: 37796556
DOI: 10.2196/48413 -
Aging Cell Oct 2023Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor...
Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.
Topics: Humans; Animals; Mice; Bloom Syndrome; Epigenesis, Genetic; Aging; Aging, Premature; Methylation; DNA Methylation
PubMed: 37594403
DOI: 10.1111/acel.13964 -
Journal of Clinical Medicine Feb 2020Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on... (Review)
Review
Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on the involved genomic landscapes. It may occur both in the germ and the somatic cells, resulting in congenital and developmental disorders and cancer, respectively. Asymptomatic individuals may be carriers of chromotriptic rearrangements and experience recurrent reproductive failures when two or more chromosomes are involved. Several mechanisms are postulated to underlie chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei, followed by the incorrect reassembly of fragments through DNA repair to explain the clustered nature of the observed complex rearrangements. Moreover, exogenous or endogenous DNA damage induction and dicentric bridge formation may be involved. Chromosome instability is commonly observed in the cells of patients with DNA repair disorders, such as ataxia telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome. In addition, germline variations of have been associated with chromothripsis in sonic hedgehog medulloblastoma and acute myeloid leukemia. In the present review, we focus on the underlying mechanisms of chromothripsis and the involvement of defective DNA repair genes, resulting in chromosome instability and chromothripsis-like rearrangements.
PubMed: 32106411
DOI: 10.3390/jcm9030613 -
Trends in Cancer Feb 2021DNA helicases have risen to the forefront as genome caretakers. Their prominent roles in chromosomal stability are demonstrated by the linkage of mutations in helicase... (Review)
Review
DNA helicases have risen to the forefront as genome caretakers. Their prominent roles in chromosomal stability are demonstrated by the linkage of mutations in helicase genes to hereditary disorders with defects in DNA repair, the replication stress response, and/or transcriptional activation. Conversely, accumulating evidence suggests that DNA helicases in cancer cells have a network of pathway interactions such that codeficiency of some helicases and their genetically interacting proteins results in synthetic lethality (SL). Such genetic interactions may potentially be exploited for cancer therapies. We discuss the roles of RECQ DNA helicases in cancer, emphasizing some of the more recent developments in SL.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; DNA Repair; DNA Replication; Gene Knockdown Techniques; Genomic Instability; Humans; Medical Oncology; Mice; Mutation; Neoplasms; Precision Medicine; RecQ Helicases; Synthetic Lethal Mutations; Xenograft Model Antitumor Assays
PubMed: 33041245
DOI: 10.1016/j.trecan.2020.09.001 -
Nucleic Acids Research Sep 2023Bloom's syndrome (BLM) protein is a known nuclear helicase that is able to unwind DNA secondary structures such as G-quadruplexes (G4s). However, its role in the...
Bloom's syndrome (BLM) protein is a known nuclear helicase that is able to unwind DNA secondary structures such as G-quadruplexes (G4s). However, its role in the regulation of cytoplasmic processes that involve RNA G-quadruplexes (rG4s) has not been previously studied. Here, we demonstrate that BLM is recruited to stress granules (SGs), which are cytoplasmic biomolecular condensates composed of RNAs and RNA-binding proteins. BLM is enriched in SGs upon different stress conditions and in an rG4-dependent manner. Also, we show that BLM unwinds rG4s and acts as a negative regulator of SG formation. Altogether, our data expand the cellular activity of BLM and shed light on the function that helicases play in the dynamics of biomolecular condensates.
Topics: Humans; DNA; G-Quadruplexes; RecQ Helicases; RNA; Stress Granules
PubMed: 37503837
DOI: 10.1093/nar/gkad613 -
Molecular Cell Jun 2021Repair pathway "choice" at stalled mammalian replication forks is an important determinant of genome stability; however, the underlying mechanisms are poorly understood....
Repair pathway "choice" at stalled mammalian replication forks is an important determinant of genome stability; however, the underlying mechanisms are poorly understood. FANCM encodes a multi-domain scaffolding and motor protein that interacts with several distinct repair protein complexes at stalled forks. Here, we use defined mutations engineered within endogenous Fancm in mouse embryonic stem cells to study how Fancm regulates stalled fork repair. We find that distinct FANCM repair functions are enacted by molecularly separable scaffolding domains. These findings define FANCM as a key mediator of repair pathway choice at stalled replication forks and reveal its molecular mechanism. Notably, mutations that inactivate FANCM ATPase function disable all its repair functions and "trap" FANCM at stalled forks. We find that Brca1 hypomorphic mutants are synthetic lethal with Fancm null or Fancm ATPase-defective mutants. The ATPase function of FANCM may therefore represent a promising "druggable" target for therapy of BRCA1-linked cancer.
Topics: Animals; BRCA1 Protein; Cell Cycle; Cell Line; Clone Cells; DNA Helicases; DNA Repair; DNA Replication; Fanconi Anemia Complementation Group D2 Protein; Fibroblasts; Humans; Mice; Mouse Embryonic Stem Cells; Synthetic Lethal Mutations; Ubiquitination
PubMed: 33882298
DOI: 10.1016/j.molcel.2021.03.044 -
Frontiers in Cell and Developmental... 2021RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These helicases play important roles in multiple cellular functions,... (Review)
Review
RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These helicases play important roles in multiple cellular functions, including DNA replication, transcription, DNA repair, and telomere maintenance. Humans have five RecQ helicases: RECQL1, Bloom syndrome protein (BLM), Werner syndrome helicase (WRN), RECQL4, and RECQL5. Defects in BLM and WRN cause autosomal disorders: Bloom syndrome (BS) and Werner syndrome (WS), respectively. Mutations in RECQL4 are associated with three genetic disorders, Rothmund-Thomson syndrome (RTS), Baller-Gerold syndrome (BGS), and RAPADILINO syndrome. Although no genetic disorders have been reported due to loss of RECQL1 or RECQL5, dysfunction of either gene is associated with tumorigenesis. Multiple genetically independent pathways have evolved that mediate the repair of DNA double-strand break (DSB), and RecQ helicases play pivotal roles in each of them. The importance of DSB repair is supported by the observations that defective DSB repair can cause chromosomal aberrations, genomic instability, senescence, or cell death, which ultimately can lead to premature aging, neurodegeneration, or tumorigenesis. In this review, we will introduce the human RecQ helicase family, describe in detail their roles in DSB repair, and provide relevance between the dysfunction of RecQ helicases and human diseases.
PubMed: 33718381
DOI: 10.3389/fcell.2021.640755