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Clinical Gastroenterology and... Jan 2024Low adherence to Mediterranean diet (MD) has been shown to be associated with a higher prevalence of irritable bowel syndrome (IBS), but its association with IBS...
BACKGROUND & AIMS
Low adherence to Mediterranean diet (MD) has been shown to be associated with a higher prevalence of irritable bowel syndrome (IBS), but its association with IBS symptoms is not established. We aim to assess the association between MD and IBS symptoms, identify components of MD associated with IBS symptoms, and determine if a symptom-modified MD is associated with changes in the gut microbiome.
METHODS
One hundred and six Rome +IBS and 108 health control participants completed diet history and gastrointestinal symptom questionnaires. Adherence to MD was measured using Alternate Mediterranean Diet and Mediterranean Diet Adherence Screener. Sparse partial least squares analysis identified MD food items associated with IBS symptoms. Stool samples were collected for 16S ribosomal RNA gene sequencing and microbial composition analysis in IBS subjects.
RESULTS
Alternate Mediterranean Diet and Mediterranean Diet Adherence Screener scores were similar between IBS and health control subjects and did not correlate with Irritable Bowel Syndrome Severity Scoring System, abdominal pain, or bloating. Among IBS participants, a higher consumption of fruits, vegetables, sugar, and butter was associated with a greater severity of IBS symptoms. Multivariate analysis identified several MD foods to be associated with increased IBS symptoms. A higher adherence to symptom-modified MD was associated with a lower abundance of potentially harmful Faecalitalea, Streptococcus, and Intestinibacter, and higher abundance of potentially beneficial Holdemanella from the Firmicutes phylum.
CONCLUSIONS
A standard MD was not associated with IBS symptom severity, although certain MD foods were associated with increased IBS symptoms. Our study suggests that standard MD may not be suitable for all patients with IBS and likely needs to be personalized in those with increased symptoms.
Topics: Humans; Irritable Bowel Syndrome; Diet, Mediterranean; Gastrointestinal Diseases; Food; Gastrointestinal Microbiome; Diet
PubMed: 37517631
DOI: 10.1016/j.cgh.2023.07.012 -
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 -
Science Advances Jul 2023The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern such as Omicron hampered efforts in controlling the ongoing coronavirus...
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern such as Omicron hampered efforts in controlling the ongoing coronavirus disease 2019 pandemic due to their ability to escape neutralizing antibodies induced by vaccination or prior infection, highlighting the need to develop broad-spectrum vaccines and therapeutics. Most human monoclonal antibodies (mAbs) reported to date have not demonstrated true pan-sarbecovirus neutralizing breadth especially against animal sarbecoviruses. Here, we report the isolation and characterization of highly potent mAbs targeting the receptor binding domain (RBD) of huACE2-dependent sarbecovirus from a SARS-CoV survivor vaccinated with BNT162b2. Among the six mAbs identified, one (E7) showed better huACE2-dependent sarbecovirus neutralizing potency and breadth than any other mAbs reported to date. Mutagenesis and cryo-electron microscopy studies indicate that these mAbs have a unique RBD contact footprint and that E7 binds to a quaternary structure-dependent epitope.
Topics: Animals; Humans; Antibodies, Viral; Neutralization Tests; BNT162 Vaccine; Severe acute respiratory syndrome-related coronavirus; Antibodies, Monoclonal; Cryoelectron Microscopy; COVID-19; SARS-CoV-2
PubMed: 37494438
DOI: 10.1126/sciadv.ade3470 -
Arthritis & Rheumatology (Hoboken, N.J.) Dec 2023This study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody...
OBJECTIVE
This study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
METHODS
Analysis of a prospective longitudinal cohort of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) in the Vasculitis Clinical Research Consortium (2013-2021). Disease cohorts were divided by age at diagnosis (years): children (<18), young adults (18-40), middle-aged adults (41-65), and older adults (>65). Data included demographics, ANCA type, clinical characteristics, Vasculitis Damage Index (VDI) scores, ANCA Vasculitis Index of Damage (AVID) scores, and novel disease-specific and non-disease-specific damage scores built from VDI and AVID items.
RESULTS
Analysis included data from 1020 patients with GPA/MPA and 357 with EGPA. Female predominance in GPA/MPA decreased with age at diagnosis. AAV in childhood was more often GPA and proteinase 3-ANCA positive. Children with GPA/MPA experienced more subglottic stenosis and alveolar hemorrhage; children and young adults with EGPA experienced more alveolar hemorrhage, need for intubation, and gastrointestinal involvement. Older adults (GPA/MPA) had more neurologic manifestations. After adjusting for disease duration, medications, tobacco, and ANCA, all damage scores increased with age at diagnosis for GPA/MPA (P < 0.001) except the disease-specific damage score, which did not differ (P = 0.44). For EGPA, VDI scores increased with age at diagnosis (P < 0.009), whereas all other scores were not significantly different.
CONCLUSION
Age at diagnosis is associated with clinical characteristics in AAV. Although VDI and AVID scores increase with age at diagnosis, this is driven by non-disease-specific damage items.
Topics: Child; Middle Aged; Young Adult; Humans; Female; Aged; Male; Antibodies, Antineutrophil Cytoplasmic; Prospective Studies; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Hemorrhage; Churg-Strauss Syndrome
PubMed: 37433067
DOI: 10.1002/art.42651 -
Journal of Translational Medicine Jul 2023Prostate cancer (PCa) is a prevalent malignant disease affecting a significant number of males globally. Elevated expression of the Bloom's syndrome protein (BLM)...
BACKGROUND
Prostate cancer (PCa) is a prevalent malignant disease affecting a significant number of males globally. Elevated expression of the Bloom's syndrome protein (BLM) helicase has emerged as a promising cancer biomarker, being associated with the onset and progression of PCa. Nevertheless, the precise molecular mechanisms governing BLM regulation in PCa remain elusive.
METHODS
The expression of BLM in human specimens was analyzed using immnohistochemistry (IHC). A 5'-biotin-labeled DNA probe containing the promoter region of BLM was synthesized to pull down BLM promoter-binding proteins. Functional studies were conducted using a range of assays, including CCK-8, EdU incorporation, clone formation, wound scratch, transwell migration, alkaline comet assay, xenograft mouse model, and H&E staining. Mechanistic studies were carried out using various techniques, including streptavidin-agarose-mediated DNA pull-down, mass spectrometry (MS), immunofluorescence (IF), dual luciferase reporter assay system, RT-qPCR, ChIP-qPCR, co-immunoprecipitation (co-IP), and western blot.
RESULTS
The results revealed significant upregulation of BLM in human PCa tissues, and its overexpression was associated with an unfavorable prognosis in PCa patients. Increased BLM expression showed significant correlations with advanced clinical stage (P = 0.022) and Gleason grade (P = 0.006). In vitro experiments demonstrated that BLM knockdown exerted inhibitory effects on cell proliferation, clone formation, invasion, and migration. Furthermore, PARP1 (poly (ADP-ribose) polymerase 1) was identified as a BLM promoter-binding protein. Further investigations revealed that the downregulation of PARP1 led to increased BLM promoter activity and expression, while the overexpression of PARP1 exerted opposite effects. Through mechanistic studies, we elucidated that the interaction between PARP1 and HSP90AB1 (heat shock protein alpha family class B) enhanced the transcriptional regulation of BLM by counteracting the inhibitory influence of PARP1 on BLM. Furthermore, the combination treatment of olaparib with ML216 demonstrated enhanced inhibitory effects on cell proliferation, clone formation, invasion, and migration. It also induced more severe DNA damage in vitro and exhibited superior inhibitory effects on the proliferation of PC3 xenograft tumors in vivo.
CONCLUSIONS
The results of this study underscore the significance of BLM overexpression as a prognostic biomarker for PCa, while also demonstrating the negative regulatory impact of PARP1 on BLM transcription. The concurrent targeting of BLM and PARP1 emerges as a promising therapeutic approach for PCa treatment, holding potential clinical significance.
Topics: Animals; Humans; Male; Mice; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Poly (ADP-Ribose) Polymerase-1; Prognosis; Prostatic Neoplasms; Up-Regulation
PubMed: 37415147
DOI: 10.1186/s12967-023-04288-z -
Journal of Athletic Training Sep 2023Persistent postconcussion symptoms (PPCSs) are associated with lower health-related quality of life (HRQoL) in children and adolescents. Despite commonly cited criteria...
CONTEXT
Persistent postconcussion symptoms (PPCSs) are associated with lower health-related quality of life (HRQoL) in children and adolescents. Despite commonly cited criteria for PPCSs involving 3 or more complaints, many individuals experience just 1 or 2 symptoms that may still negatively affect HRQoL.
OBJECTIVE
To determine differences in HRQoL between children and adolescents with 0, 1 to 2, or 3+ parent-reported persistent symptoms at 1 month postconcussion.
DESIGN
Prospective cohort study.
SETTING
Community practice clinics.
PATIENTS OR OTHER PARTICIPANTS
Individuals aged 8 to 18 years presented for the initial visit within 3 days of a sport- or recreation-related concussion. One month later, parents or guardians reported persistent symptoms using the Rivermead Post Concussion Symptoms Questionnaire (RPQ). Individuals with complete symptom data were analyzed (n = 236/245, n = 97 females, age = 14.3 ± 2.1 years). Participants were grouped by the number of discrete RPQ symptoms reported as worse than preinjury (0, 1-2, or 3+).
MAIN OUTCOME MEASURE(S)
Total summary and subscale scores on the Pediatric Quality of Life Inventory (PedsQL) 23-item HRQoL inventory and 18-item Multidimensional Fatigue Scale (MDFS).
RESULTS
Kruskal-Wallis rank sum tests highlighted differences in PedsQL HRQoL and MDFS total scores across symptom groups (PedsQL HRQoL: χ22 = 85.53, P < .001; MDFS: χ22 = 93.15, P < .001). Dunn post hoc analyses indicated all 3 groups were statistically significantly different from each other (P < .001). The median (interquartile range) values for the Peds QL Inventory HRQoL totals were 93.5 (84.2-98.8) for those with 0 symptoms; 84.8 (73.9-92.4) for those with 1 to 2 symptoms; and 70.7 (58.7-78.0) for those with 3+ symptoms. The median (interquartile range) values for the MDFS totals were 92.4 (76.4-98.6) for those with 0 symptoms; 78.5 (65.6-88.9) for those with 1 to 2 symptoms; and 54.2 (46.2-65.3) for those with 3+ symptoms. Similar group differences were observed for each PedsQL HRQoL and MDFS subscale score.
CONCLUSIONS
Children and adolescents whose parents reported 1 to 2 PPCSs had lower HRQoL and more fatigue than those with 0 symptoms. Across all 3 groups, those with 3+ persistent symptoms had the lowest HRQoL and most fatigue. These findings indicate the continued need for intervention in this age group to prevent and address PPCSs.
Topics: Female; Humans; Child; Adolescent; Post-Concussion Syndrome; Quality of Life; Prospective Studies; Brain Concussion; Sports
PubMed: 37347117
DOI: 10.4085/1062-6050-0552.22 -
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 -
Cell Reports Jun 2023Continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is eroding antibody responses elicited by prior vaccination and infection. The...
Continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is eroding antibody responses elicited by prior vaccination and infection. The SARS-CoV-2 receptor-binding domain (RBD) E406W mutation abrogates neutralization mediated by the REGEN-COV therapeutic monoclonal antibody (mAb) COVID-19 cocktail and the AZD1061 (COV2-2130) mAb. Here, we show that this mutation remodels the receptor-binding site allosterically, thereby altering the epitopes recognized by these three mAbs and vaccine-elicited neutralizing antibodies while remaining functional. Our results demonstrate the spectacular structural and functional plasticity of the SARS-CoV-2 RBD, which is continuously evolving in emerging SARS-CoV-2 variants, including currently circulating strains that are accumulating mutations in the antigenic sites remodeled by the E406W substitution.
Topics: Humans; SARS-CoV-2; Combined Antibody Therapeutics; COVID-19; Antibodies, Viral; Antibodies, Neutralizing; Antibodies, Monoclonal; Spike Glycoprotein, Coronavirus; Neutralization Tests
PubMed: 37300832
DOI: 10.1016/j.celrep.2023.112621