Abstract
Background
Fragmentomics, the investigation of fragmentation patterns of cell-free DNA (cfDNA), has emerged as a promising strategy for the early detection of multiple cancers in the field ...of liquid biopsy. However, the clinical application of this approach has been hindered by a limited understanding of cfDNA biology. Furthermore, the prevalence of hematopoietic cell-derived cfDNA in plasma complicates the in vivo investigation of tissue-specific cfDNA other than that of hematopoietic origin. While conventional two-dimensional cell lines have contributed to research on cfDNA biology, their limited representation of in vivo tissue contexts underscores the need for more robust models. In this study, we propose three-dimensional organoids as a novel in vitro model for studying cfDNA biology, focusing on multifaceted fragmentomic analyses.
Results
We established nine patient-derived organoid lines from normal lung airway, normal gastric, and gastric cancer tissues. We then extracted cfDNA from the culture medium of these organoids in both proliferative and apoptotic states. Using whole-genome sequencing data from cfDNA, we analyzed various fragmentomic features, including fragment size, footprints, end motifs, and repeat types at the end. The distribution of cfDNA fragment sizes in organoids, especially in apoptosis samples, was similar to that found in plasma, implying occupancy by mononucleosomes. The footprints determined by sequencing depth exhibited distinct patterns depending on fragment sizes, reflecting occupancy by a variety of DNA-binding proteins. Notably, we discovered that short fragments (< 118 bp) were exclusively enriched in the proliferative state and exhibited distinct fragmentomic profiles, characterized by 3 bp palindromic end motifs and specific repeats.
Conclusions
In conclusion, our results highlight the utility of in vitro organoid models as a valuable tool for studying cfDNA biology and its associated fragmentation patterns. This, in turn, will pave the way for further enhancements in noninvasive cancer detection methodologies based on fragmentomics.
Objective
We evaluated the frequency, risk factors and the follow‐up outcomes of thyroid nodules, and genetic alterations in thyroid cancer, in youth with childhood‐onset Hashimoto thyroiditis (HT) ...residing in an iodine‐sufficient country.
Design
A retrospective cohort study.
Patients and measurements
A total of 213 patients (194 females, mean age 10.6 years at the time of HT diagnosis) were ultrasonographically evaluated. Thyroid nodules were categorized using the Korean Thyroid Imaging Reporting and Data System (K‐TIRADS) and the American College of Radiology Thyroid Imaging Reporting and Data System (ACR‐TI‐RADS).
Results
Thyroid nodules were detected in 40 (18.8%) patients over a median follow‐up period of 3.4 years, usually after the onset of puberty. A family history of thyroid disease (hazard ratio 2.1, p = .031) was predictive of thyroid nodule detection. Papillary thyroid carcinoma (PTC) was diagnosed in 9 (4.2% of all and 22.5% of nodule‐positive patients). The malignant nodules had a higher K‐TIRADS or ACR‐TI‐RADS risk level compared with benign nodules (p < .01 for both). Genetic alterations were revealed in 7 (BRAFV600E in 6 and RET‐ERC1 fusion in 1) of the eight available tumour tissue samples. None showed evidence of disease over a median follow‐up period of 3.4 years.
Conclusions
The nodule detection rate was 18.8%, with a 22.5% risk of malignancy among the detected nodules in childhood‐onset HT patients, showing increased risk in those with a family history. Additional large‐scale studies are required to evaluate the usefulness of K‐TIRADS or ACR‐TI‐RADS risk level for the differentiation of paediatric thyroid nodules.
Atrial fibrillation (AF) is associated with various major adverse cardiac events such as ischemic stroke, heart failure, and increased overall mortality. However, its association with lethal ...ventricular arrhythmias such as ventricular tachycardia (VT), ventricular flutter (VFL), and ventricular fibrillation (VF) is controversial. We conducted this study to determine whether AF can increase the risk of VT, VFL, and VF. We utilized the Korean National Health Insurance Service database for this nationwide population-based study. This study enrolled people who underwent a nationwide health screen in 2009 for whom clinical follow-up data were available until December 2018. Primary outcome endpoint was the occurrence of VT, VFL, or VF in people who were and were not diagnosed with new-onset AF in 2009. We analyzed a total of 9,751,705 people. In 2009, 12,689 people were diagnosed with new-onset AF (AF group). The incidence (events per 1000 person-years of follow-up) of VT, VFL, and VF was 2.472 and 0.282 in the AF and non-AF groups, respectively. After adjustment for covariates, new-onset AF was associated with 4.6-fold increased risk (p < 0.001) of VT, VFL, and VF over 10 years of follow-up. The risk of VT, VFL, and VF was even higher if identification of AF was based on intensified criteria (≥ 2 outpatient records or ≥ 1 inpatient record; hazard ratio = 5.221; p < 0.001). In conclusion, the incidence of VT, VFL, and VF was significantly increased in people with new-onset AF. The potential risk of suffering lethal ventricular arrhythmia in people with AF should be considered in clinical practice.
The cell is constructed by higher-order structures and organelles through complex interactions among distinct structural constituents. The centrosome is a membraneless organelle composed of two ...microtubule-derived structures called centrioles and an amorphous mass of pericentriolar material. Super-resolution microscopic analyses in various organisms revealed that diverse pericentriolar material proteins are concentrically localized around a centriole in a highly organized manner. However, the molecular nature underlying these organizations remains unknown. Here we show that two human pericentriolar material scaffolds, Cep63 and Cep152, cooperatively generate a heterotetrameric α-helical bundle that functions in conjunction with its neighboring hydrophobic motifs to self-assemble into a higher-order cylindrical architecture capable of recruiting downstream components, including Plk4, a key regulator for centriole duplication. Mutations disrupting the self-assembly abrogate Plk4-mediated centriole duplication. Because pericentriolar material organization is evolutionarily conserved, this work may offer a paradigm for investigating the assembly and function of centrosomal scaffolds in various organisms.
Here, we present the Northeast Asian Reference Database (NARD), including whole-genome sequencing data of 1779 individuals from Korea, Mongolia, Japan, China, and Hong Kong. NARD provides the genetic ...diversity of Korean (n = 850) and Mongolian (n = 384) ancestries that were not present in the 1000 Genomes Project Phase 3 (1KGP3). We combined and re-phased the genotypes from NARD and 1KGP3 to construct a union set of haplotypes. This approach established a robust imputation reference panel for Northeast Asians, which yields the greatest imputation accuracy of rare and low-frequency variants compared with the existing panels. NARD imputation panel is available at https://nard.macrogen.com/ .
The incidence of sudden cardiac arrest (SCA) in Asians is lower than that seen in Western populations, but there are few available data on the incidence and associated cardiac etiology of SCA in ...Asians. From 2002 to 2013, patients with SCA were analyzed using a cohort from the South Korean National Health Insurance Service (NHIS) coded database. Sudden unexplained death syndrome (SUDS) was defined as cryptogenic arrest, excluding that of non-cardiac origin, coronary artery disease (CAD), cardiomyopathy (CM), and valvular heart disease. During the 12-year study period, 5,973 patients (0.53%) from the total cohort of 1,125,691 had a cardiac arrest code. The overall incidence of arrest was 48.7 per 100,000 person-years (95% CI 16.6-18.0). The incidence of primary SCA excluding those of non-cardiac origin was 16.1 per 100,000 person-years (95% CI 15.4-16.8). It was higher in males than in females (18.1 vs. 14.1 per 100,000 person-years). CAD was the most common cause of SCA (59.4%), and followed by CM (13.9%). SUDS accounted for 14.7% of SCA events. The risk of SCA had increased gradually from over 25 years old. Heart failure, atrial fibrillation and hypertension are major factors associated with SCA incidence. Our findings outline epidemiologic data for SCA and the proportion of associated cardiac etiology leads SCA in a large population.
Actinic keratosis (AK) is a common precancerous skin lesion that can develop into cutaneous squamous cell carcinoma (CSCC). AK is characterized by atypical keratinocytes in the skin's outer layer and ...is commonly found in sun-exposed areas. Like many precancerous lesions, the development of AK is closely associated with genetic mutations. The molecular biology and transcriptional mechanisms underlying AK development are not well understood. Ultraviolet (UV) light exposure, especially UVA and UVB radiation, is a significant risk factor for AK, causing DNA damage and mutagenic effects. Besides UV exposure, comorbidities like diabetes, rheumatoid arthritis, and psoriasis may also influence AK development. AK patients have shown associations with various internal malignancies, indicating potential vulnerability in cancer-associated genes. Treatment for AK includes cryosurgery, electrodesiccation and curettage, chemotherapeutic creams, photodynamic therapy, or topical immune-modulators. Genomic studies have identified genetic aberrations in AK, with common mutations found in genes like
,
, and
. The progression from AK to CSCC involves chromosomal aberrations and alterations in oncogenes and tumor-suppressor genes. The functional relationships among these genes are not fully understood, but network analysis provides insights into their potential mechanisms. Further research is needed to enhance our understanding of AK's pathogenesis and develop novel therapeutic approaches.
Beta-blockers are first-line therapy in patients with congenital long-QT syndrome (LQTS).
This study sought to determine the differences in effectiveness of beta-blockers on risk reduction according ...to LQTS genotype.
We searched MEDLINE, EMBASE, and CENTRAL databases to investigate the use of beta-blockers (atenolol, nadolol, propranolol, and metoprolol) in patients with LQTS. Hazard ratio (HR) and relative risk (RR) were extracted or calculated from studies reporting cardiac events (syncope, aborted cardiac arrest (ACA), or sudden cardiac death (SCD)).
Among 2,113 articles searched, 10 studies (7 registry-based cohort studies (Cohort) and 3 interrupted time series studies (ITS)) involving 9,727 patients were included. In a meta-analysis using a random-effect model, the use of beta-blocker was associated with significant risk reduction of all cardiac events (HR 0.49, p<0.001 in Cohort; RR 0.39, p<0.001 in ITS) and serious cardiac events (ACA or SCD) (HR 0.47, p<0.001 in Cohort). In both LQT1 and LQT2, the risk was reduced with beta-blocker therapy in Cohort (HR 0.59 in LQT1; HR 0.39 in LQT2) as well as ITS (RR 0.29 in LQT1; RR 0.48 in LQT2). Among the beta-blockers, nadolol showed a significant risk reduction in both LQT1 and LQT2 (HR 0.47 and 0.27, respectively), whereas atenolol and propranolol decreased the risk only in LQT1 (HR 0.36 and 0.46, respectively). Metoprolol showed no significant reduction in either genotype. In LQT3, beta-blocker therapy was not as effective as LQT1 or LQT2; however, it was inconclusive due to data insufficiency.
This meta-analysis showed that beta-blockers were effective in reducing risk of cardiac events in patients with LQTS. Among them, nadolol was effective in LQT1 and LQT2, whereas other drugs showed different effectiveness depending on LQT genotype.
Being obese or underweight, and having diabetes are important risk factors for new-onset atrial fibrillation (AF). However, it is unclear whether there is any interaction between body weight and ...diabetes in regard to development of new-onset AF. We aimed to evaluate the role of body weight status and various stage of diabetes on new-onset AF.
This was a nationwide population based study using National Health Insurance Service (NHIS) data. A total of 9,797,418 patients who underwent national health check-ups were analyzed. Patients were classified as underweight body mass index (BMI) < 18.5, normal reference group (18.5 ≤ BMI < 23.0), upper normal (23.0 ≤ BMI < 25.0), overweight (25.0 ≤ BMI < 30.0), or obese (BMI ≥ 30.0) based on BMI. Diabetes were categorized as non-diabetic, impaired fasting glucose (IFG), new-onset diabetes, diabetes < 5 years, and diabetes ≥ 5 years. Primary outcome end point was new-onset AF. New-onset AF was defined as one inpatient or two outpatient records of International Classification of Disease, Tenth Revision (ICD-10) codes in patients without prior AF diagnosis.
During 80,130,161 patient*years follow-up, a total of 196,136 new-onset AF occurred. Obese hazard ration (HR) = 1.327, overweight (HR = 1.123), upper normal (HR = 1.040), and underweight (HR = 1.055) patients showed significantly increased risk of new-onset AF compared to the normal reference group. Gradual escalation in the risk of new-onset AF was observed along with advancing diabetic stage. Body weight status and diabetes were independently associated with new-onset AF and at the same time, had synergistic effects on the risk of new-onset AF with obese diabetic patients having the highest risk (HR = 1.823).
Patients with obesity, overweight, underweight, and diabetes had significantly increased risk of new-onset AF. Body weight status and diabetes had synergistic effects on the risk of new-onset AF. The risk of new-onset AF increased gradually with advancing diabetic stage. This study suggests that maintaining optimal body weight and glucose homeostasis might prevent new-onset AF.
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