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Journal of Cell Communication and... Sep 2023Prostate cancer (PCa) has long been the leading cause of cancer-associated deaths among male worldwide. Our previous studies have shown that Bloom syndrome protein (BLM)...
Prostate cancer (PCa) has long been the leading cause of cancer-associated deaths among male worldwide. Our previous studies have shown that Bloom syndrome protein (BLM) plays a vital role in PCa proliferation, yet the underlying molecular mechanism remains largely obscure. Mechanistically, BLM directly interacted with hepatoma-derived growth factor (HDGF). Functionally, BLM and HDGF knockdown resulted in the higher impairment of PC3 proliferation, clonogenicity, migration and invasion than that their counterpart with either BLM or HDGF knockdown exclusively. Of note, HDGF overexpression expedited, whereas its knockdown suppressed, PC3 proliferation, clonogenicity, migration and invasion. Additionally, the potentiation or attenuation was partially antagonized upon BLM depletion or overexpression. In line with the vitro data, the impact of BLM and HDGF on tumor growth was investigated in mouse xenograft models. ChIP-seq, dual-luciferase reporter and western blotting assays were employed to expound the regulatory network in PC3 cells. The results unveiled that HDGF activated KRAS and suppressed RhoA transcription, and that the function of HDGF was mediated, in part, by interaction with BLM. Accordingly, the MAPK/ERK pathway was activated. Moreover, the regulation of HDGF on KRAS and RhoA had a signal crosstalk. To recapitulate, BLM and HDGF may serve as novel prognostic markers and potential therapeutic targets in PCa.
PubMed: 36574142
DOI: 10.1007/s12079-022-00717-8 -
Nature Communications Jun 2024Homology-dependent targeted DNA integration, generally referred to as gene targeting, provides a powerful tool for precise genome modification; however, its fundamental...
Homology-dependent targeted DNA integration, generally referred to as gene targeting, provides a powerful tool for precise genome modification; however, its fundamental mechanisms remain poorly understood in human cells. Here we reveal a noncanonical gene targeting mechanism that does not rely on the homologous recombination (HR) protein Rad51. This mechanism is suppressed by Rad52 inhibition, suggesting the involvement of single-strand annealing (SSA). The SSA-mediated gene targeting becomes prominent when DSB repair by HR or end-joining pathways is defective and does not require isogenic DNA, permitting 5% sequence divergence. Intriguingly, loss of Msh2, loss of BLM, and induction of a target-site DNA break all significantly and synergistically enhance SSA-mediated targeted integration. Most notably, SSA-mediated integration is cell cycle-independent, occurring in the G1 phase as well. Our findings provide unequivocal evidence for Rad51-independent targeted integration and unveil multiple mechanisms to regulate SSA-mediated targeted as well as random integration.
Topics: Humans; Rad51 Recombinase; Rad52 DNA Repair and Recombination Protein; Gene Targeting; Cell Cycle; MutS Homolog 2 Protein; RecQ Helicases; Homologous Recombination; DNA Breaks, Double-Stranded; DNA Repair; DNA End-Joining Repair; G1 Phase
PubMed: 38890315
DOI: 10.1038/s41467-024-49385-9 -
Open Heart Mar 2024Coronary CT angiography (CCTA) permits both qualitative and quantitative analysis of atherosclerotic plaque and may be a suitable risk modifier in assessing patients at...
OBJECTIVE
Coronary CT angiography (CCTA) permits both qualitative and quantitative analysis of atherosclerotic plaque and may be a suitable risk modifier in assessing patients at intermediate risk of atherosclerotic cardiovascular disease. We sought to determine the association of plaque components with long-term major adverse cardiovascular events (MACEs) in asymptomatic intermediate-risk patients, compared with conventional coronary artery calcium (CAC) score.
METHODS
100 intermediate-risk patients underwent double-blinded CCTA. Follow-up was conducted at 10 years and data were cross-referenced with the National Death Index. The primary outcome was MACE, which was a composite of death, acute coronary syndrome (ACS), revascularisation and stroke.
RESULTS
The median time from CCTA to follow-up was 9.5 years. 83 patients completed follow-up interview and mortality data were available on all 100 patients. MACE occurred in 17 (20.5%) patients, which included 2 (2%) deaths, 8 (10%) ACS, 3 (4%) strokes and 5 (6%) revascularisation procedures. 47 (57%) patients had mixed plaque, which was predictive of MACE (OR 4.68 (95% CI 1.19 to 18.5) p=0.028). The burden of non-calcified and mixed plaque, defined by non-calcified plaque segment stenosis score, was also a predictor of long-term MACE (OR 1.59 (95% CI 1.18 to 2.13) p=0.002). Neither calcified plaque (OR 3.92 (95% CI 0.80 to 19.3)) nor CAC score (OR 1.01 (95% CI 0.999 to 1.02)) was associated with long-term MACE.
CONCLUSION
The presence and burden of mixed plaque on CCTA is associated with an increased risk of long-term MACE among asymptomatic intermediate-risk patients and is a superior predictor to CAC score.
Topics: Humans; Plaque, Atherosclerotic; Computed Tomography Angiography; Prognosis; Coronary Angiography; Tomography, X-Ray Computed; Atherosclerosis; Acute Coronary Syndrome
PubMed: 38458771
DOI: 10.1136/openhrt-2024-002609 -
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 -
BMJ Open Apr 2024We aimed to assess the healthcare costs and impact on the economy at large arising from emergency medical services (EMS) treated non-traumatic shock.
OBJECTIVES
We aimed to assess the healthcare costs and impact on the economy at large arising from emergency medical services (EMS) treated non-traumatic shock.
DESIGN
We conducted a population-based cohort study, where EMS-treated patients were individually linked to hospital-wide and state-wide administrative datasets. Direct healthcare costs (Australian dollars, AUD) were estimated for each element of care using a casemix funding method. The impact on productivity was assessed using a Markov state-transition model with a 3-year horizon.
SETTING
Patients older than 18 years of age with shock not related to trauma who received care by EMS (1 January 2015-30 June 2019) in Victoria, Australia were included in the analysis.
PRIMARY AND SECONDARY OUTCOME MEASURES
The primary outcome assessed was the total healthcare expenditure. Secondary outcomes included healthcare expenditure stratified by shock aetiology, years of life lived (YLL), productivity-adjusted life-years (PALYs) and productivity losses.
RESULTS
A total of 21 334 patients (mean age 65.9 (±19.1) years, and 9641 (45.2%) females were treated by EMS with non-traumatic shock with an average healthcare-related cost of $A11 031 per episode of care and total cost of $A280 million. Annual costs remained stable throughout the study period, but average costs per episode of care increased (P=0.05). Among patients who survived to hospital, the average cost per episode of care was stratified by aetiology with cardiogenic shock costing $A24 382, $A21 254 for septic shock, $A19 915 for hypovolaemic shock and $A28 057 for obstructive shock. Modelling demonstrated that over a 3-year horizon the cohort lost 24 355 YLLs and 5059 PALYs. Lost human capital due to premature mortality led to productivity-related losses of $A374 million. When extrapolated to the entire Australian population, productivity losses approached $A1.5 billion ($A326 million annually).
CONCLUSION
The direct healthcare costs and indirect loss of productivity among patients with non-traumatic shock are high. Targeted public health measures that seek to reduce the incidence of shock and improve systems of care are needed to reduce the financial burden of this syndrome.
Topics: Humans; Female; Male; Victoria; Aged; Health Care Costs; Middle Aged; Emergency Medical Services; Cost of Illness; Aged, 80 and over; Shock; Cohort Studies; Adult; Quality-Adjusted Life Years; Health Expenditures
PubMed: 38684259
DOI: 10.1136/bmjopen-2023-078435 -
Cell Reports. Medicine Jun 2024Little is known about the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS2) vaccine breakthrough infections (BTIs) on the magnitude and...
Little is known about the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS2) vaccine breakthrough infections (BTIs) on the magnitude and breadth of the T cell repertoire after exposure to different variants. We studied samples from individuals who experienced symptomatic BTIs during Delta or Omicron waves. In the pre-BTI samples, 30% of the donors exhibited substantial immune memory against non-S (spike) SARS2 antigens, consistent with previous undiagnosed asymptomatic SARS2 infections. Following symptomatic BTI, we observed (1) enhanced S-specific CD4 and CD8 T cell responses in donors without previous asymptomatic infection, (2) expansion of CD4 and CD8 T cell responses to non-S targets (M, N, and nsps) independent of SARS2 variant, and (3) generation of novel epitopes recognizing variant-specific mutations. These variant-specific T cell responses accounted for 9%-15% of the total epitope repertoire. Overall, BTIs boost vaccine-induced immune responses by increasing the magnitude and by broadening the repertoire of T cell antigens and epitopes recognized.
Topics: Humans; SARS-CoV-2; COVID-19; Epitopes, T-Lymphocyte; CD8-Positive T-Lymphocytes; CD4-Positive T-Lymphocytes; COVID-19 Vaccines; Spike Glycoprotein, Coronavirus; Immunologic Memory; Female; Adult; Male; Mutation; Middle Aged; T-Lymphocytes; Breakthrough Infections
PubMed: 38781962
DOI: 10.1016/j.xcrm.2024.101583 -
Ophthalmic Surgery, Lasers & Imaging... Jun 2024
Review
Topics: Humans; Geographic Atrophy; Shaken Baby Syndrome; Infant; Complement Inactivating Agents
PubMed: 38860971
DOI: 10.3928/23258160-20240523-01 -
Antioxidants (Basel, Switzerland) Feb 2024Obesity and metabolic dysfunction have been shown to be associated with overproduction of reactive oxygen species (ROS) in the gastrointestinal (GI) tract, which...
Obesity and metabolic dysfunction have been shown to be associated with overproduction of reactive oxygen species (ROS) in the gastrointestinal (GI) tract, which contributes to dysbiosis or imbalances in the gut microbiota. Recently, the reversal of dysbiosis has been observed as a result of dietary supplementation with antioxidative compounds including polyphenols. Likewise, dietary polyphenols have been associated with scavenging of GI ROS, leading to the hypothesis that radical scavenging in the GI tract is a potential mechanism for the reversal of dysbiosis. The objective of this study was to investigate the relationship between GI ROS, dietary antioxidants and beneficial gut bacterium . The results of this study demonstrated to be a discriminant microorganism between lean ( = 7) and obese ( = 7) mice. The relative abundance of was also found to have a significant negative correlation with extracellular ROS in the GI tract as measured using fluorescent probe hydroindocyanine green. The ability of the dietary antioxidants ascorbic acid, β-carotene and grape polyphenols to scavenge GI ROS was evaluated in tandem with their ability to support bloom in lean mice ( = 20). While the relationship between GI ROS and relative abundance of was conserved in lean mice, only grape polyphenols stimulated the bloom of . Analysis of fecal antioxidant capacity and differences in the bioavailability of the antioxidants of interest suggested that the poor bioavailability of grape polyphenols contributes to their superior radical scavenging activity and support of in comparison to the other compounds tested. These findings demonstrate the utility of the GI redox environment as a modifiable therapeutic target in the treatment of chronic inflammatory diseases like metabolic syndrome.
PubMed: 38539838
DOI: 10.3390/antiox13030304 -
The Journal of Molecular Diagnostics :... Mar 2024Prenatal molecular genetic testing for familial variants that cause inherited disorders has been performed for decades and is accepted as standard of care. However, the...
Prenatal molecular genetic testing for familial variants that cause inherited disorders has been performed for decades and is accepted as standard of care. However, the spectrum of genes considered for prenatal testing is expanding because of genetic testing for hereditary cancer risk (HCR) and inclusion of conditions with associated cancer risk in carrier screening panels. A few of these disorders, such as ataxia telangiectasia and Bloom syndrome, include increased cancer risk as part of the phenotype, already meet professional guidelines for prenatal testing, and may be associated with increased cancer risk in heterozygous carriers. In addition, recent studies implicate heterozygosity for variants in lysosomal storage disease genes in HCR etiology. Currently, there is no specific professional guidance regarding prenatal testing for HCR. To determine the prevalence of such testing, we reviewed 1345 consecutive prenatal specimens received in our laboratory for familial variant-specific testing and identified 65 (4.8%) with a known or likely HCR component, plus 210 (15.6%) for lysosomal storage disease. These specimens were classified into five distinct categories for clarity and to enable evaluation. Our experience assessing prenatal specimens for variants associated with HCR, with or without a constitutional phenotype, provides metrics for and contributes to the points to consider in prenatal testing for HCR.
Topics: Female; Humans; Pregnancy; Genetic Predisposition to Disease; Genetic Testing; Lysosomal Storage Diseases; Neoplasms; Phenotype
PubMed: 38171482
DOI: 10.1016/j.jmoldx.2023.12.002 -
Kidney International Reports Jun 2024Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with (Spalt like Transcription Factor 1), is reported to be present in 1:238,000...
INTRODUCTION
Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with (Spalt like Transcription Factor 1), is reported to be present in 1:238,000 individuals in the general population. TBS is characterized by the triad of anorectal malformations, dysplastic ears, with or without hearing impairment, and hand or thumb anomalies. Although kidney involvement is less common in TBS, the disease can progress to kidney failure. Here, we sought to characterize the incidence of variants in individuals undergoing broad-based genetic testing with a kidney gene panel and to quantify the presence of (extra)renal features.
METHODS
A retrospective analysis of the genetic data from a 385-gene panel identified cases with a pathogenic (P) or likely pathogenic (LP) variant in . Data including age, features, and disease progression were collected.
RESULTS
Of 35,044 samples, P or LP variants in were identified in 22, yielding a prevalence of 1:1592 among patients tested for monogenic kidney disease, and 1:342 among cases identified with a monogenic kidney disease. Among this cohort, the median patient age was 23 years (range: 3 months-62 years) with chronic kidney disease (CKD) reported in 91% (20/22) of cases. Reported kidney features included renal agenesis/hypoplasia (7/22; 32%), focal segmental glomerulosclerosis (4/22; 18%), and kidney cysts (3/22; 14%). Confirmed extrarenal features included hearing loss and/or ear features (7/22; 32%), anorectal malformations (6/22; 27%) and hand or thumb abnormalities (4/22; 18%). Three patients (3/22; 14%) had both TBS diagnoses and the traditional "triad."
CONCLUSION
Traditionally, a molecular diagnosis was ascertained primarily in individuals presenting with cardinal features of TBS; therefore, individuals with mild or atypical presentations were often overlooked clinically. Our findings reveal that P/LP variants could be a consequential contributor to monogenic kidney disease.
PubMed: 38899216
DOI: 10.1016/j.ekir.2024.03.030