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Background: Comprehensive medication management (CMM) programs optimize the effectiveness and safety of patients' medication regimens, but CMM may be underutilized. Whether healthcare claims data can identify patients appropriate for CMM is not well-studied., Aim: Determine the face validity of a claims-based algorithm to prioritize patients who likely need CMM., Method: We used claims data to construct patient-level markers of "regimen complexity" and "high-risk for adverse effects," which were combined to define four categories of claims-based CMM-need (very likely, likely, unlikely, very unlikely) among 180 patient records. Three clinicians independently reviewed each record to assess CMM need. We assessed concordance between the claims-based and clinician-review CMM need by calculating percent agreement as well as kappa statistic., Results: Most records identified as 'very likely' (90%) by claims-based markers were identified by clinician-reviewers as needing CMM. Few records within the 'very unlikely' group (5%) were identified by clinician-reviewers as needing CMM. Interrater agreement between CMM-based algorithm and clinician review was moderate in strength (kappa = 0.6, p < 0.001)., Conclusion: Claims-based pharmacy measures may offer a valid approach to prioritize patients into CMM-need groups. Further testing of this algorithm is needed prior to implementation in clinic settings., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Previous cross-sectional studies have shown that higher magnesium intake is associated with better cognitive function, particularly in individuals with sufficient vitamin D status. The aim of this study was to evaluate the longitudinal associations between magnesium intake and cognitive impairment in a community-based cohort study in Taiwan., Methods: The study population included 5663 community-dwelling adults aged ≥ 55 years old recruited from 2009 to 2013 and followed up from 2013 to 2020. Magnesium intake was evaluated from a validated food frequency questionnaire at baseline. Cognitive performance was measured at baseline and follow-up for participants' Mini-Mental Status Examination (MMSE), Digit Symbol Substitution Test (DSST), and Clock-Drawing Test (CDT), and impairment was defined as MMSE < 24, DSST < 21, and CDT < 3, respectively. Multivariate logistic regression models were used to examine the associations and were stratified by sex and plasma vitamin D levels (≥ 50 or < 50 nmol/L)., Results: Higher baseline magnesium intake was associated with lower odds of a poor performance on the MMSE in both men and women (4th vs. 1st. quartile: OR = 0.43, 95% CI = 0.23-0.82, p trend  < 0.01 in men and OR = 0.53, 95% CI = 0.29-0.97, p trend  = 0.12 in women) and on the DSST in men (OR = 0.23, 95% CI = 0.09-0.61, p trend  < 0.01) at follow-up. Inverse associations between baseline magnesium intake and a poor performance on the MMSE or DSST were observed in men regardless of vitamin D status., Conclusion: Our study suggested that higher magnesium intake was associated with the development of cognitive impairment in men in a median follow-up period of 6 years., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite the promising potential of direct central nervous system (CNS) antibody administration to enhance brain exposure, there remains a significant gap in understanding the disposition of antibodies following different intra-CNS injection routes. To bridge this knowledge gap, this study quantitatively investigated the brain pharmacokinetics (PK) of antibodies following intra-CNS administration. The microdialysis samples from the striatum (ST), cerebrospinal fluid (CSF) samples through cisterna magna (CM) puncture, plasma, and brain homogenate samples were collected to characterize the pharmacokinetics (PK) profiles of a non-targeting antibody, trastuzumab, following intracerebroventricular (ICV), intracisternal (ICM), and intrastriatal (IST) administration. For a comprehensive analysis, these intra-CNS injection datasets were juxtaposed against our previously acquired intravenous (IV) injection data obtained under analogous experimental conditions. Our findings highlighted that direct CSF injections, either through ICV or ICM, resulted in ~ 5-6-fold higher interstitial fluid (ISF) drug exposure than IV administration. Additionally, the low bioavailability observed following IST administration indicates the existence of a local degradation process for antibody elimination in the brain ISF along with the ISF bulk flow. The study further refined a physiologically based pharmacokinetic (PBPK) model based on new observations by adding the perivascular compartments, oscillated CSF flow, and the nonspecific uptake and degradation of antibodies by brain parenchymal cells. The updated model can well characterize the antibody PK following systemic and intra-CNS administration. Thus, our research offers quantitative insight into antibody brain disposition pathways and paves the way for determining optimal dosing and administration strategies for antibodies targeting CNS disorders., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Immune checkpoint inhibitors such as anti-PD-1 antibodies (aPD1) can be effective in treating advanced cancers. However, many patients do not respond and the mechanisms underlying these differences remain incompletely understood. In this study, we profile a cohort of patients with locally-advanced or metastatic basal cell carcinoma undergoing aPD-1 therapy using single-cell RNA sequencing, high-definition spatial transcriptomics in tumors and draining lymph nodes, and spatial immunoreceptor profiling, with long-term clinical follow-up. We find that successful responses to PD-1 inhibition are characterized by an induction of B-cell receptor (BCR) clonal diversity after treatment initiation. These induced BCR clones spatially co-localize with T-cell clones, facilitate their activation, and traffic alongside them between tumor and draining lymph nodes to enhance tumor clearance. Furthermore, we validated aPD1-induced BCR diversity as a predictor of clinical response in a larger cohort of glioblastoma, melanoma, and head and neck squamous cell carcinoma patients, suggesting that this is a generalizable predictor of treatment response across many types of cancers. We discover that pre-treatment tumors harbor a characteristic gene expression signature that portends a higher probability of inducing BCR clonal diversity after aPD-1 therapy, and we develop a machine learning model that predicts PD-1-induced BCR clonal diversity from baseline tumor RNA sequencing. These findings underscore a dynamic role of B cell diversity during immunotherapy, highlighting its importance as a prognostic marker and a potential target for intervention in non-responders.

The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is based mainly on clinical presentations, and the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NETs) to investigate axonal membrane properties and chemical precipitation, followed by ELISA analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-voltage threshold curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the current-voltage threshold curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72 or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely to be associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the current-voltage threshold curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partly prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes to familial ALS patients and ALS mice with mutant SOD1, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the current-voltage threshold curve was attributable to an elevation in the HCN current in SOD1-associated ALS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: The Social Detachment Questionnaire for the Older Population (SDQO) is a validated tool that assesses various dimensions of social relationships. This study aimed to profile social detachment among older people in Taiwan using the SDQO and explore its use in distinguishing groups with varying levels of social engagement., Methods: A telephone-based survey was conducted, collecting demographic data and responses to the SDQO and Brief Symptom Rating Scale-5 (BSRS-5). Cluster analysis based on SDQO dimension scores was performed to identify groupings. Regression analyses examined the association between social engagement clusters, demographic variables, and BSRS-5 scores. A receiver operating characteristic curve was established and the area under the curve was calculated to identify the cutoff for distinguishing individuals with high and low social engagement., Results: In a representative sample of 2549 individuals aged 55 and above in Taiwan, cluster analysis identified two groups based on social engagement levels as measured by the SDQO. The low social engagement cluster, indicating higher social detachment, was more likely to consist of older individuals (≥ 75 years), those without children, and those with lower education levels (≤ 9 years). After adjusting for demographics, the low social engagement cluster was associated with higher BSRS-5 scores. The optimal SDQO cutoff for identifying low social engagement was 27/28., Conclusions: The SDQO can identify socially detached older people, who are more likely to experience increased psychological distress. Screening older individuals with demographic risk factors using the SDQO could help identify those most vulnerable to adverse health outcomes related to social detachment., (© 2024 John Wiley & Sons Ltd.)

Introduction: Real-world data are needed to understand the effectiveness of new therapeutic options for low-density lipoprotein cholesterol (LDL-C) reduction in Asia-Pacific clinical practice. Description of evolocumab use among adults with establisHed Atherosclerotic cardiovascuLar diseasE or hypercholesterolemia in ASia-Pacific region (HALES) was performed to better understand characteristics of and clinical decision-making for adults with established atherosclerotic cardiovascular disease/hypercholesterolemia after local evolocumab approval., Methods: The HALES observational study, conducted at 33 sites (Hong Kong, Thailand, South Korea, Singapore, Taiwan, and Australia) comprised (1) chart review of patients who received evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), and (2) physician/patient survey and one-time data collection of patients with high cardiovascular risk initiating evolocumab or initiating/continuing non-PCSK9i lipid-lowering therapy. Patients could only enroll in (1) or (2)., Results: Chart review included 724 very high-risk patients initiating evolocumab from regulatory approval to 2021. From median baseline LDL-C of 3.2 mmol/L (123.7 mg/dL), patients had a median percent change in LDL-C of - 60.8% at 1-6 months. Goal achievement increased from 7.9% to 69.8% for < 1.8 mmol/L (< 70 mg/dL) and 4.4% to 57.8% for < 1.4 mmol/L (< 55 mg/dL) from baseline to 12 months. In the one-time data collection, more patients had ≥ 1.8 mmol/L (≥ 70 mg/dL) baseline LDL-C in the evolocumab vs non-PCSK9i group (95.2% and 48.5%, respectively). Surveys found that physicians applied guideline-recommended treatment targets, and patients demonstrated gaps in understanding cardiovascular risk., Conclusion: Real-world, Asia-Pacific data showed that LDL-C reduction after initiating evolocumab was consistent with that observed in other clinical trials and patient populations. Graphical abstract available for this article.·., Competing Interests: Declarations. Conflict of Interest: Hung-Fat Tse reports research funding from Abbott, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, Medtronic, Novartis, Pfizer, and Sanofi. Hung-Yu Chang, Kian Keong Poh, Karam Kostner, and Pisit Hutayanon report that they have nothing to declare. David Colquhoun reports research funding from Amgen, Pfizer, AstraZeneca, Novartis, Sanofi, Bayer, and Novo Nordisk. Jung-Sun Kim reports receiving proctoring fees from Abbott Vascular. Meejin Cho, Jeff Lange, Kamlanathan Kodiappan, and Saikiran Leekha are employees and stockholders of Amgen Inc. Ethics Approval: Informed consent was required for patient’s participation in the study. Study protocol and informed consent forms were reviewed and approved by the institutional review board/independent ethics committee (see Supplementary Materials, Supplemental Table S2 for full list by site). Central IRBs were used for sites in Australia and Singapore; local IRBD/ethics committees were used in all other sites. The study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments., (© 2024. The Author(s).)

Aim: To examine the main effects and interaction effects of outcome expectations (e.g., anticipated satisfactory salary and benefits), nurse identity (a sense of membership in the nursing profession), and information-access efficiency of the electronic medical record system (how the system enables nurses to quickly retrieve the needed information) on nurses' retention., Design: This study uses a cross-sectional survey and adopts proportionate random sampling to recruit a representative sample of nurses of a medical centre in Taiwan., Methods: This study successfully obtained completed questionnaires from 430 nurses during December 2021 to January 2022. Data are analysed by using hierarchical regressions., Results: Positive outcome expectations and identification as a member in the nursing profession are associated with retention. Information-access efficiency strengthens the link between outcome expectations and retention, while nurse identity weakens this link., Conclusion: Outcome expectations can help retain nurses, particularly those who perceive high levels of information-access efficiency and possess weak nurse identity. That is, outcome expectations have a complementary role with nurse identity in retaining nurses., Implications for the Profession: Nurse managers should devise means to build positive outcome expectations for nurses. In addition, either strengthening nurses' identification with the nursing profession or improving the information-access efficiency of the electronic medical system may also help retain nurses., Impact: This study examined how to transform outcome expectation to nurse retention, offering nurse managers to devise new means to retain nurses., Reporting Method: STROBE statement was chosen as EQUATOR checklist., Patient or Public Contribution: No patient or public contribution., (© 2024 John Wiley & Sons Ltd.)

Integrins, the receptors of the extracellular matrix, are critical in the proliferation and metastasis of cancer cells. GMI, a Ganoderma microsporum immunomodulatory protein, possesses anticancer and antivirus abilities. The object of this study is to investigate the role of GMI in the integrins signaling pathway in lung cancer cells that harbor the EGFR L858R/T790M double mutation and osimertinib-resistance. Liquid chromatography-mass spectrometry and western blot assay were used to investigate the effect of GMI on inhibiting the protein expressions of integrins in H1975 cells. The migration ability and xenograft tumor growth of H1975 were suppressed by GMI. To elucidate the role of the integrin family in lung cancer resistant to osimertinib (AZD-9291, Tagrisso), H1975 cells were used to establish the osimertinib-resistant cells, named H1975/TR cells. The expressions of Integrin αV and stemness markers were much higher in H1975/TR cells than in H1975 cells. GMI suppressed cell viability, tumor spheroid growth, and the expressions of integrin αV and β1 in H1975/TR cells. Furthermore, GMI suppressed the expressions of stemness markers and formation of tumor spheres via blocking integrin αV signaling cascade. This is the first study to reveal the novel function of GMI in constraining cancer stem cells and migration by abolishing the integrin αV-related signaling pathway in EGFR-mutated and osimertinib-resistant lung cancer cells., (© 2024 Wiley Periodicals LLC.)

Background: Social detachment includes the subjective aspect "loneliness" and the objective aspect "social isolation," but tools to assess both dimensions are limited. This study aims to develop a questionnaire, the Social Detachment Questionnaire for Older Population (SDQO), that considers multiple dimensions of social detachment simultaneously., Methods: The study collected 600 valid samples from individuals aged 55 and above to examine the psychometric properties of the developed SDQO. Item analysis was conducted to assess the performance of each item, and exploratory factor analysis (EFA) was employed to analyze its initial structure and eliminate less ideal items. Subsequently, confirmatory factor analysis (CFA) was used to examine the model fit of the suggested structure by EFA, using different subsamples. Internal consistency, concurrent validity, and other analyses were also performed., Results: The original 27-item SDQO was reduced to 17 items after removing 4 questions in item analysis and 6 questions in EFA. The Cronbach's alpha for the 17-item version of SDQO was 0.80. Both EFA and CFA supported its 6-factor structure, with factors identified as community activities, loneliness, personal resources, leisure activities, friendship, and family resources. SDQO also demonstrated expected performance in concurrent validity., Conclusion: The 17-item version of SDQO exhibited good reliability and validity, measuring various aspects of social detachment behavior, feelings, and resources. It holds value for future research applications., Competing Interests: Declaration of competing interest The authors report no conflicts with any product mentioned or concept discussed in this article., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Aim: To investigate whether education, tenure, being an advanced practice nurse, skill level, and time pressure impact perceptions of "having a place" and, further, turnover intentions., Background: Nursing shortages persist worldwide. Nurses' turnover intentions are negatively related to their perceptions of "having a place" (i.e., the feeling that the nursing workplace is their territory). However, the sources of nurses' perceptions of the perception of "having a place" remain unknown., Methods: Our research employed a cross-sectional and correlational design. This research was conducted at a large-scale hospital in northern Taiwan from December 2021 to January 2022. We used personnel data pertaining to 430 nurses as well as scales for time pressure, "having a place" and turnover intentions to assess nurses' intention to leave their place of employment. The inclusion criteria focused on full-time nurses who worked for the hospital under investigation. Most of our participants were women. The STROBE statement was used as the EQUATOR checklist (supplemental file)., Results: "Having a place" was positively related to educational level, tenure, and skill level, while being an advanced practice nurse was negatively associated with perceptions of "having a place," which in turn were negatively related to turnover intention among nurses., Conclusion: Our study is the first to examine the antecedents of nurses' perceptions of "having a place," which include education, tenure, and skill level., Implications for Nursing Policy: Nursing policymakers could encourage nurses to pursue higher degrees and update their nursing skills while instilling perceptions of "having a place" in nurses with a brief tenure and advanced practice nurses., (© 2024 International Council of Nurses.)

Background: Literature on the safety of remdesivir in hospitalized COVID-19 patients with severe renal impairment is limited. We aimed to investigate the safety and effectiveness of remdesivir in this population., Methods: We conducted a retrospective cohort study of adult hospitalized COVID-19 patients who received remdesivir between April 2022 and October 2022. Outcomes were compared between estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 and ≥30 mL/min/1.73 m 2 groups. The primary safety outcomes were acute kidney injury (AKI) and bradycardia, while the primary effectiveness outcomes included mortality in COVID-19-dedicated wards and hospital mortality. Secondary outcomes included laboratory changes, disease progression, and recovery time., Results: A total of 1,343 patients were recruited, with 307 (22.9%) in the eGFR <30 group and 1,036 (77.1%) in the eGFR ≥30 group. Patients with an eGFR <30 had higher risks of AKI (adjusted hazard ratio [aHR] 2.92, 95% CI 1.93-4.44) and hospital mortality (aHR 1.47, 95% CI 1.06-2.05) but had comparable risks of bradycardia (aHR 1.15, 95% CI 0.85-1.56) and mortality in dedicated wards (aHR 1.43, 95% CI 0.90-2.28) than patients with an eGFR ≥30. Risk of disease progression was higher in the eGFR <30 group (adjusted odds ratio 1.62, 95% CI 1.16-2.26). No difference between the two groups in laboratory changes and recovery time., Conclusions: Hospitalized COVID-19 patients receiving remdesivir with severe renal impairment had an increased risk of AKI, hospital mortality, and COVID-19 disease progression compared to patients without severe renal impairment.

Objective: This study compared the differences in the rates of maltreatment and homicide deaths between children and young adults with and without a life-limiting condition (LLC) and determined whether this affects the likelihood of receiving specialised palliative care (SPC) services before death., Design: A nationwide retrospective observational study., Setting: Taiwan., Patients: Children and young adults aged 0-25 years with LLCs and maltreatment were identified within the Health and Welfare Data Science Centre by International Classification of Diseases codes. Deaths were included within the Multiple Causes of Death Data if they occurred between 2016 and 2017., Main Outcome Measures: Rates of maltreatment, homicide deaths and SPC referrals., Results: Children and young adults with underlying LLCs experienced a similar rate of maltreatment (2.2 per 10 000 vs 3.1 per 10 000) and had a 68% decrease in the odds of homicide death (19.7% vs 80.3%, OR, 0.32; 95% CI 0.18 to 0.56) than those without such conditions. Among those with LLCs who experienced maltreatment, 14.3% (2 out of 14) had received SPC at least 3 days before death. There was no significant difference in SPC referrals between those who experienced maltreatment and those who did not., Conclusions: The likelihood of being referred to SPC was low with no significant statistical differences observed between children and young adults with maltreatment and without. These findings suggest a need for integrating SPC and child protection services to ensure human rights are upheld., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cyanobacteria are diverse phototrophic microbes with ecological importance and potential for biotechnology applications. One species of thermophilic cyanobacteria, Thermosynechococcus taiwanensis, has been studied for biomass pyrolysis, estrogen degradation, and the production of bioethanol, monosaccharide, and phycocyanin. To better understand the diversity and evolution of this species, we sampled across different regions in Taiwan for strain isolation and genomic analysis., Results: A total of 27 novel strains were isolated from nine of the 12 hot springs sampled and subjected to whole genome sequencing. Including strains studied previously, our genomic analyses encompassed 32 strains from 11 hot springs. Genome sizes among these strains ranged from 2.64 to 2.70 Mb, with an average of 2.66 Mb. Annotation revealed between 2465 and 2576 protein-coding genes per genome, averaging 2537 genes. Core-genome phylogeny, gene flow estimates, and overall gene content divergence consistently supported the within-species divergence into two major populations. While isolation by distance partially explained the within-population divergence, the factors driving divergence between populations remain unclear. Nevertheless, this species likely has a closed pan-genome comprising approximately 3030 genes, with our sampling providing sufficient coverage of its genomic diversity. To investigate the divergence and potential adaptations, we identified genomic regions with significantly lower nucleotide diversity, indicating loci that may have undergone selective sweeps within each population. We identified 149 and 289 genes within these regions in populations A and B, respectively. Only 16 genes were common to both populations, suggesting that selective sweeps primarily targeted different genes in the two populations. Key genes related to functions such as photosynthesis, motility, and ion transport were highlighted., Conclusions: This work provides a population genomics perspective on a hot spring cyanobacterial species in Taiwan. Beyond advancing our understanding of microbial genomics and evolution, the strains collected and genome sequences generated in this work provide valuable materials for future development and utilization of biological resources., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. CHK is a Senior Editor of Botanical Studies at the time of submission., (© 2024. The Author(s).)

For vegetarians or vegan athletes, improving the utilization of plant-based protein and the absorption of amino acids is crucial. This study explored the impact of combining pea protein with Lactiplantibacillus plantarum TWK10 and resistance training on amino acid absorption and exercise performance. Sixteen male and sixteen female participants were randomly assigned to either a control group (20 g of pea protein without TWK10) or a TWK10 group (20 g of pea protein combined with 1 × 10 10  colony-forming units of TWK10). After 28 days of supplementation combined with resistance exercise training three times per week. All subjects underwent body composition and muscle strength performance, plasma and fecal samples were collected for microbiota analysis and blood amino acid concentrations. The TWK10 group showed a significant increase in muscle thickness and improvements were observed in 1 repetition maximum bench press, explosive, anaerobic power output compared to before the intervention, and were significantly higher than those in the control group ( p  < 0.05). TWK10 supplementation significantly increased the area under the curve and maximum concentration of branched-chain amino acids, essential amino acids, and total amino acids ( p  < 0.05). Furthermore, TWK10 supplementation effectively increased the richness of gut bacterial families. Our study demonstrated that the TWK10 significant increase in the abundance of specific bacterial families in the gut, resulting in increased pea protein amino acid absorption. Moreover, increasing muscle mass and significantly improving muscle thickness, muscle strength, power, and anaerobic capacity., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yi-Chu Liao reports a relationship with Culture Collection & Research Institute, SYNBIO TECH INC that includes: employment. Yi-Chen Cheng reports a relationship with Culture Collection & Research Institute, SYNBIO TECH INC that includes: employment. Chia-Chia Lee reports a relationship with Culture Collection & Research Institute, SYNBIO TECH INC that includes: employment. Jin-Seng Lin reports a relationship with Culture Collection & Research Institute, SYNBIO TECH INC that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Melon (Cucumis melo L.), an important cucurbit crop, faces production limitations due to powdery mildew (PM). Developing resistant varieties offers a sustainable, genetics-based alternative to chemical treatments. Therefore, identifying PM resistance quantitative trait loci (QTL) and creating trait-associated markers are essential for efficient melon PM resistance improvement through marker-assisted backcrossing (MABC)., Results: Three F 2 populations, A6, B2, and C4, were generated for QTL mapping of PM resistance. Major QTL were identified on chromosome 2 in A6, chromosome 5 in B2, and chromosomes 5 and 12 in C4. A series of TaqMan® assays targeting regions on chromosomes 2, 5, and 12 were developed and validated for foreground and recombinant selection, complemented by the double digest restriction-site associated DNA genotyping system to evaluate the recurrent parent genome recovery. Three MABC programs using resistant donor parents from A6 and C4 crossed with elite susceptible recurrent parents with green and orange fruit flesh were implemented. After two to three cycles of MABC, individual QTL was successfully introgressed into elite genetic backgrounds, giving six PM resistance lines in each green- and orange-fleshed background. PM inoculation on the twelve near-isogenic lines confirmed their resistance to PM., Conclusions: We have identified major PM resistance QTL for melon on chromosomes 2, 5, and 12 and have introgressed individual QTL to elite genetic backgrounds using MABC in three and a half years. This study demonstrates the power of combining high-throughput genotyping with breeding efforts and showcases the efficiency of molecular breeding., (© 2024. The Author(s).)

For the primary prevention of atherosclerotic cardiovascular disease (ASCVD), the recommended treatment target for each modifiable risk factor is as follows: reducing body weight by 5-10%; blood pressure < 130/80 mmHg (systolic pressure < 120 mmHg in high-risk individuals); low-density lipoprotein cholesterol (LDL-C) < 100 mg/dL in high-risk individuals, LDL-C < 115 mg/dL in moderate-risk individuals, LDL-C < 130 mg/dL in low-risk individuals, and LDL-C < 160 mg/dL in those with a minimal; complete and persistent abstinence from cigarette smoking; hemoglobin A1C < 7.0%; fulfilling recommended amounts of the six food groups according to the Taiwan food guide; and moderate-intensity physical activity 150 min/wk or vigorous physical activity 75 min/wk. For the primary prevention of ASCVD by pharmacological treatment in individuals with modifiable risk factors/clinical conditions, statins are the first-line therapy for reducing LDL-C levels; some specific anti-diabetic drugs proven to be effective in randomized controlled trials for the primary prevention of ASCVD are recommended in patients with type 2 diabetes mellitus; pharmacological treatment is recommended to assist in weight management for obese patients with a body mass index ≥ 30 kg/m 2 (or 27 kg/m 2 who also have at least one ASCVD risk factor or obesity-related comorbidity); an angiotensin-converting enzyme inhibitor, a glucagon-like peptide-1 receptor agonist, a sodium-dependent glucose cotransporter-2 inhibitor, and finerenone can be used in diabetic patients with chronic kidney disease for the primary prevention of ASCVD. Of note, healthcare providers are at full discretion in clinical practice, owing to the diversity of individuals and practice, and the availability of resources and facilities., Competing Interests: Ting-Hsing Chao has been on the speaker bureau for Astrazeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Novartis, Pfizer, Sanofi, Tanabe, and TSH biopharm. All other authors report no potential conflicts of interest in relation to these guidelines.

The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently 1 . Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division 2,3 . Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells 4 . How multiple ecDNA species within a tumour cell are assorted and maintained across somatic cell generations is unclear. Here we show that cooperative ecDNA species are coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. ecDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy-number gains in multiple ecDNA species before any selection. Intermolecular proximity and active transcription at the start of mitosis facilitate the coordinated segregation of ecDNA species, and transcription inhibition reduces co-segregation. Computational modelling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations., (© 2024. The Author(s).)

Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer 1,2 . Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans. We also identify intrinsic and environmental mutational processes linked to ecDNA, including those linked to its formation, such as tobacco exposure, and progression, such as homologous recombination repair deficiency. Clinically, ecDNA detection was associated with tumour stage, more prevalent after targeted therapy and cytotoxic treatments, and associated with metastases and shorter overall survival. These results shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumour growth signals, alter transcriptional landscapes and suppress the immune system., (© 2024. The Author(s).)

Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival 1-7 . At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription-replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA, leading to excessive transcription-replication conflicts and replication stress compared with chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and replication stress is significantly higher in ecDNA-containing tumours regardless of cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds single-stranded DNA, shows elevated localization on ecDNA in a transcription-dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, CHK1. Genetic or pharmacological CHK1 inhibition causes extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent and bioavailable oral CHK1 inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric cancer model containing FGFR2 amplified on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription-replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer., (© 2024. The Author(s).)

Interhomolog recombination in meiosis requires a meiosis-specific recombinase, Dmc1. In Saccharomyces cerevisiae, the Mei5-Sae3 complex facilitates the loading of Dmc1 onto the replication protein A (RPA)-coated single-stranded DNA (ssDNA) to form nucleoprotein filaments. In vivo, Dmc1 and Mei5-Sae3 are interdependent in their colocalization on the chromosomes. However, the mechanistic role of Mei5-Sae3 in mediating Dmc1 activity remains unclear. We used single-molecule fluorescence resonance energy transfer and colocalization single-molecule spectroscopy experiments to elucidate how Mei5-Sae3 stimulates Dmc1 assembly on ssDNA and RPA-coated ssDNA. We showed that Mei5-Sae3 stabilized Dmc1 nucleating clusters with two to three molecules on naked DNA by preferentially reducing Dmc1 dissociation rates. Mei5-Sae3 also stimulated Dmc1 assembly on RPA-coated DNA. Using green fluorescent protein-labeled RPA, we showed the coexistence of an intermediate with Dmc1 and RPA on ssDNA before RPA dissociation. Moreover, the displacement efficiency of RPA depended on Dmc1 concentration, and its dependence was positively correlated with the stability of Dmc1 clusters on short ssDNA. These findings suggest a molecular model that Mei5-Sae3 mediates Dmc1 binding on RPA-coated ssDNA by stabilizing Dmc1 nucleating clusters, thus altering RPA dynamics on DNA to promote RPA dissociation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Homologous recombination during meiosis is critical for chromosome segregation and also gives rise to genetic diversity. Genetic exchange between homologous chromosomes during meiosis is mediated by the recombinase Dmc1, which is capable of recombining DNA sequences with mismatches. The Hop2-Mnd1 complex mediates Dmc1 activity. Here, we reveal a regulatory role for Hop2-Mnd1 in restricting substrate selection. Specifically, Hop2-Mnd1 upregulates Dmc1 activity with DNA substrates that are either fully homologous or contain DNA mismatches, and it also acts against DNA strand exchange between substrates solely harboring microhomology. By isolating and examining salient Hop2-Mnd1 separation-of-function variants, we show that suppressing illegitimate DNA recombination requires the Dmc1 filament interaction attributable to Hop2-Mnd1 but not its DNA binding activity. Our study provides mechanistic insights into how Hop2-Mnd1 helps maintain meiotic recombination fidelity., (© 2024. The Author(s).)

Thyroid cancer (TC) is one of the most prevalent endocrine malignancy with a steadily increasing incidence globally. Although standard treatments like thyroidectomy and radioiodine therapy effectively manage most cases of differentiated thyroid cancers (DTC), certain recurrent cases or those involving poorly differentiated thyroid cancers (PDTC) demand more specialized interventions. Follicular thyroid cancer (FTC) is the second most common type of DTC, and frequently metastasizes through the bloodstream to distant sites such as bones and lungs which is a leading cause of metastatic and recurrent DTC and significantly affects survival. However, existing drugs primarily address symptom management without offering a curative solution. Therefore, it is urgent to develop a new therapeutic agent for these challenging cases. Evodiamine (EVO), extracted from Evodia rutaecarpa , has shown potential as an anti-cancer agent in multiple types of human cancers including anaplastic thyroid cancer (ATC) and papillary thyroid cancer (PTC) cells. However, the anti-cancer effects of EVO on FTC have remained unclear. Therefore, the present study aims to investigate the anti-cancer effects of EVO in FTC cells. Our data showed that EVO effectively inhibits FTC cell growth, induces cell cycle arrest, and triggers apoptosis. Additionally, our study explored the underlying mechanisms through which EVO affects signaling pathways. To verify the anti-cancer effects of combination chemotherapy, EVO and doxorubicin were used together in FTC cells. In conclusion, this study demonstrates that EVO shows significant anti-human FTC activity, making it a promising therapeutic candidate for the treatment of follicular thyroid cancers., Competing Interests: None., (AJCR Copyright © 2024.)

Oncogene amplification on extrachromosomal DNA (ecDNA) is strongly associated with treatment resistance and shorter survival for patients with cancer, including patients with glioblastoma. The non-chromosomal inheritance of ecDNA during cell division is a major contributor to intratumoral genetic heterogeneity. At present, the spatial dynamics of ecDNA, and the impact on tumor evolutionary trajectories, are not well understood. Here, we investigate the spatial-temporal evolution of ecDNA and its clinical impact by analyzing tumor samples from 94 treatment-naive human IDH -wildtype glioblastoma patients. We developed a spatial-temporal computational model of ecDNA positive tumors ('SPECIES') that integrates whole-genome sequencing, multi-region DNA FISH, and nascent RNAscope, to provide unique insight into the spatial dynamics of ecDNA evolution. Random segregation in combination with positive selection of ecDNAs induce large, predictable spatial patterns of cell-to-cell ecDNA copy number variation that are highly dependent on the oncogene encoded on the circular DNA. EGFR ecDNAs often reach high mean copy number (mean of 50 copies per tumor cell), are under strong positive selection (mean selection coefficient, s > 2) and do not co-amplify other oncogenes on the same ecDNA particles. In contrast, PDGFRA ecDNAs have lower mean copy number (mean of 15 copies per cell), are under weaker positive selection and frequently co-amplify other oncogenes on the same ecDNA. Evolutionary modeling suggests that EGFR ecDNAs often accumulate prior to clonal expansion. EGFR structural variants, including vIII and c-terminal deletions are under strong positive selection, are found exclusively on ecDNA, and are intermixed with wild-type EGFR ecDNAs. Simulations show EGFRvIII ecDNA likely arises after ecDNA formation in a cell with high wild-type EGFR copy number (> 10) before the onset of the most recent clonal expansion. This remains true even in cases of co-selection and co-amplification of multiple oncogenic ecDNA species in a subset of patients. Overall, our results suggest a potential time window in which early ecDNA detection may provide an opportunity for more effective intervention., Highlights: ecDNA is the most common mechanism of focal oncogene amplification in IDH wt glioblastoma. EGFR and its variants on ecDNA are particularly potent, likely arising early in tumor development, providing a strong oncogenic stimulus to drive tumorigenesis. Wild-type and variant EGFR ecDNA heteroplasmy (co-occurrence) is common with EGFR vIII or c-terminal deletions being derived from EGFR wild-type ecDNA prior to the most recent clonal expansion. Tumors with ecDNA amplified EGFR versus PDGFRA exhibit different evolutionary trajectories. SPECIES model can infer spatial evolutionary dynamics of ecDNA in cancer.A delay between ecDNA accumulation and subsequent oncogenic mutation may give a therapeutic window for early intervention.

Tumor progression is driven by dynamic interactions between cancer cells and their surrounding microenvironment. Investigating the spatiotemporal evolution of tumors can provide crucial insights into how intrinsic changes within cancer cells and extrinsic alterations in the microenvironment cooperate to drive different stages of tumor progression. Here, we integrate high-resolution spatial transcriptomics and evolving lineage tracing technologies to elucidate how tumor expansion, plasticity, and metastasis co-evolve with microenvironmental remodeling in a Kras;p53 -driven mouse model of lung adenocarcinoma. We find that rapid tumor expansion contributes to a hypoxic, immunosuppressive, and fibrotic microenvironment that is associated with the emergence of pro-metastatic cancer cell states. Furthermore, metastases arise from spatially-confined subclones of primary tumors and remodel the distant metastatic niche into a fibrotic, collagen-rich microenvironment. Together, we present a comprehensive dataset integrating spatial assays and lineage tracing to elucidate how sequential changes in cancer cell state and microenvironmental structures cooperate to promote tumor progression., Competing Interests: DECLARATION OF INTERESTS M.G.J. consults for and has equity in Vevo Therapeutics. K.E.Y. is a consultant for Cartography Biosciences. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, and a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. T.J. is the President of Break Through Cancer. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. J.S.W. declares outside interest in 5 AM Venture, Amgen, Chroma Medicine, KSQ Therapeutics, Maze Therapeutics, Tenaya Therapeutics, Tessera Therapeutics, Ziada Therapeutics, DEM Biopharma, and Third Rock Ventures. D.Y. declares outside interest in DEM Biopharma.

Extrachromosomal DNA (ecDNA) is a central mechanism for focal oncogene amplification in cancer, occurring in ∼15% of early-stage cancers and ∼30% of late-stage cancers. ecDNAs drive tumor formation, evolution, and drug resistance by dynamically modulating oncogene copy number and rewiring gene-regulatory networks. Elucidating the genomic architecture of ecDNA amplifications is critical for understanding tumor pathology and developing more effective therapies. Paired-end short-read (Illumina) sequencing and mapping have been utilized to represent ecDNA amplifications using a breakpoint graph, in which the inferred architecture of ecDNA is encoded as a cycle in the graph. Traversals of breakpoint graphs have been used to successfully predict ecDNA presence in cancer samples. However, short-read technologies are intrinsically limited in the identification of breakpoints, phasing together complex rearrangements and internal duplications, and deconvolution of cell-to-cell heterogeneity of ecDNA structures. Long-read technologies, such as from Oxford Nanopore Technologies, have the potential to improve inference as the longer reads are better at mapping structural variants and are more likely to span rearranged or duplicated regions. Here, we propose Complete Reconstruction of Amplifications with Long reads (CoRAL) for reconstructing ecDNA architectures using long-read data. CoRAL reconstructs likely cyclic architectures using quadratic programming that simultaneously optimizes parsimony of reconstruction, explained copy number, and consistency of long-read mapping. CoRAL substantially improves reconstructions in extensive simulations and 10 data sets from previously characterized cell lines compared with previous short- and long-read-based tools. As long-read usage becomes widespread, we anticipate that CoRAL will be a valuable tool for profiling the landscape and evolution of focal amplifications in tumors., (© 2024 Zhu et al.; Published by Cold Spring Harbor Laboratory Press.)

Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. Chemical genetic screens combined with isothermal dose-response fingerprinting and mass spectrometry identified a small molecule SP2509 that specifically inhibits Pirin-mediated hTERT reactivation in colorectal cancers by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat and increased incidence of colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic. Significance: We show how iron-(Fe3+) in collusion with genetic factors reactivates telomerase, providing a molecular mechanism for the association between iron overload and increased incidence of colorectal cancers. Although no enzymatic inhibitors of telomerase have entered the clinic, we identify SP2509, a small molecule that targets telomerase reactivation and function in colorectal cancers., (©2024 The Authors; Published by the American Association for Cancer Research.)

Importance: Clinicians are a key component of preexposure prophylaxis (PrEP) care. Yet, no prior studies have quantitatively investigated how PrEP adherence differs by clinician specialty., Objective: To understand the association between prescribing clinician specialty and patients not picking up (reversal/abandonment) their initial PrEP prescription., Design, Setting, and Participants: This cross-sectional study of patients who were 18 years or older used pharmacy claims data from 2015 to 2019 on new insurer-approved PrEP prescriptions that were matched with clinician data from the US National Plan and Provider Enumeration System. Data were analyzed from January to May 2022., Main Outcomes and Measures: Clinician specialties included primary care practitioners (PCPs), infectious disease (ID), or other specialties. Reversal was defined as a patient not picking up their insurer-approved initial PrEP prescription. Abandonment was defined as a patient who reversed and still did not pick their prescription within 365 days., Results: Of the 37 003 patients, 4439 (12%) were female and 32 564 (88%) were male, and 77% were aged 25 to 54 years. A total of 24 604 (67%) received prescriptions from PCPs, 3571 (10%) from ID specialists, and 8828 (24%) from other specialty clinicians. The prevalence of reversals for patients of PCPs, ID specialists, and other specialty clinicians was 18%, 18%, and 25%, respectively, and for abandonments was 12%, 12%, and 20%, respectively. After adjusting for confounding, logistic regression models showed that, compared with patients who were prescribed PrEP by a PCP, patients prescribed PrEP by ID specialists had 10% lower odds of reversals (odds ratio [OR], 0.90; 95% CI, 0.81-0.99) and 12% lower odds of abandonment (OR, 0.88; 95% CI, 0.78-0.98), while patients prescribed by other clinicians had 33% higher odds of reversals (OR, 1.33; 95% CI, 1.25-1.41) and 54% higher odds of abandonment (OR, 1.54; 95% CI, 1.44-1.65)., Conclusion: The results of this cross-sectional study suggest that PCPs do most of the new PrEP prescribing and are a critical entry point for patients. PrEP adherence differs by clinician specialties, likely due to the populations served by them. Future studies to test interventions that provide adherence support and education are needed.

Background: Male hypogonadism is not uncommon in people with HIV (PWH), with estimated prevalence ranging from 9% to 16%. Existing data are limited on the serum testosterone levels in PWH in Asian populations., Methods: We enrolled HIV-positive men who have sex with men (MSM) and had been on stable antiretroviral therapy and MSM without HIV between February 2021 and November 2022. Serum free testosterone levels, sex hormone-binding globulins and other associated hormones were measured. Multiple linear regression analysis was performed to assess the association between serum free testosterone levels and clinical variables collected., Results: A total of 447 MSM with HIV and 124 MSM without HIV were enrolled. Compared with MSM without HIV, MSM with HIV had a higher age (median, 41 versus 29.5 years) and prevalence of symptomatic hypogonadism (8.3% versus 1.6%). Among MSM who were aged <35 years, there were no significant differences in the serum free testosterone levels and prevalences of hypogonadism between the two groups. In multiple linear regression analysis, serum free testosterone level significantly decreased with advanced age (a decrease of 1.14 pg/mL per 1-year increase) and a higher body-mass index (BMI) (a decrease of 1.07 pg/mL per 1-kg/m 2 increase), but was not associated with HIV serostatus., Conclusion: We found that MSM with HIV had a higher prevalence of symptomatic hypogonadism than MSM without HIV in Taiwan, which could be attributed to age difference. Serum free testosterone levels were negatively correlated with age and BMI, but did not show a significant correlation with HIV serostatus., Competing Interests: Declaration of competing interest CCH has received honoraria for speaking at educational events or consulting from Gilead Sciences, and research funding from Gilead Sciences. HYS has received research funding from Gilead Sciences. The remaining authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and showed that STAG2 is uniquely tumor-suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo, and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. STAG2 inactivation elicits changes in gene expression, chromatin accessibility, and 3D genome conformation that impact the cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relate STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin-mediated mechanisms of lung tumor suppression., (© 2024 Ashkin et al.)

Amplification of human epidermal growth factor 2 receptor (HER2) and overexpression of estrogen receptor (ER) and/or progesterone receptor (PR) are key determinants in the treatment planning for human breast cancer (BC). Currently, targeted therapies for BC are focused mainly on these biomarkers. However, development of resistance to targeted drugs is almost unavoidable, emphasizing the importance of biochemical and pharmaceutical advances to improve treatment outcomes. To the best of our knowledge, the present study is the first to show functional crosstalk in vitro between HER2 and epithelial membrane protein 3 (EMP3), a tetraspan membrane protein, in human BC. EMP3 overexpression significantly promoted BC cell proliferation, invasion and migration by Transwell assays via epithelial-mesenchymal transition and transactivated the HER family, resulting in increased ER and PR expression in vitro . Knocking down EMP3 notably suppressed cell proliferation and migration and was accompanied by decreased expression of HER1‑HER3 and p‑SRC proteins. Suppression of EMP3 expression enhanced sensitivity of BC cells to trastuzumab in vitro . Xenograft experiments revealed decreased expression of HER1 and HER2 in stable EMP3‑knockdown cells, resulting in decreased tumor weight and size. In patients with BC, EMP3 overexpression was detected in 72 of 166 cases (43.4%), with 18 of 43 (41.9%) HER2‑amplified BC samples co‑expressing EMP3. Co‑expression of EMP3 and HER2 was positively associated with ER expression (P=0.028) and tended to be associated with nodal metastasis (P=0.085), however this was not significant. Taken together, the present results supported the potential of targeting EMP3 as a novel therapeutic strategy for human BC via co‑expression of HER2 and EMP3.

Objectives: This retrospective study evaluates the effectiveness of pulsed dye laser (PDL) treatment in early versus late treatment groups for traumatic or postoperative scars. The study aims to determine the threshold between early and late treatment. Additionally, it investigates factors that may influence wound healing outcomes., Methods: The medical records of 147 patients who underwent PDL treatment at our institution between January 2018 and December 2022 were retrospectively reviewed. Inclusion criteria were patients receiving PDL treatment for traumatic or postoperative scars. Out of these patients, we selected those who were willing to receive telephone interviews or re-visit at a scheduled time. Eventually, 52 participants were included in our study. A standardized questionnaire was administered to all participants during telephone interviews, encompassing inquiries regarding their medical history, treatment experiences, and the patient component of the Patient and Observer Scar Assessment Scale. Among the enrolled patients, 38 were contacted and interviewed via telephone, while the remaining 14 patients attended follow-up visits where photographs of their current skin condition were captured. The pretreatment and latest follow-up photographs obtained from the clinical database were independently scored in a blinded manner by two dermatologist reviewers using both the Vancouver Scar Scale and the Manchester Scar Scale., Results: Among the 52 patients, 43 (82.7%) were successfully treated with good response. The correlation coefficients between week-to-treatment initiation and posttreatment MSS and VSS among patients with good response were 0.50 (p < 0.001) and 0.46 (p = 0.002), respectively. Given these findings, we established a treatment initiation threshold of 10 weeks, distinguishing patients into early and late treatment groups. The early treatment group showed borderline significantly lower posttreatment MSS and VSS scores than the late treatment group (MSS: 7.5 ± 2.1 vs. 9.3 ± 2.5, p = 0.011; VSS: 2.8 ± 2.0 vs. 4.5 ± 2.3, p = 0.011). Furthermore, both MSS and VSS of posttreatment showed significantly greater improvement in the early treatment group (4.4 ± 1.6 vs. 3.2 ± 1.9; p = 0.03 and 3.8 ± 1.8 vs. 2.8 ± 1.4; p = 0.04)., Conclusions: Early intervention using a PDL within 10 weeks post-injury achieved better outcomes in treating traumatic and postoperative scars based on both clinical and patient opinions., (© 2024 Wiley Periodicals LLC.)

The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and show that STAG2 is uniquely tumor suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo , and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo . STAG2 inactivation elicits changes in gene expression, chromatin accessibility and 3D genome conformation that impact cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relates STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin mediated mechanisms of lung tumor suppression., Summary: STAG2 is a frequently mutated cohesin subunit across several cancers and one of the most important functional suppressors of lung adenocarcinoma. Our findings underscore important roles of STAG2 in suppressing lung tumorigenesis and highlight a STAG2-PAXIP1/PAGR1 tumor-suppressive program that may transcend cancer type.

Extrachromosomal DNA (ecDNA) is a hallmark of aggressive cancer, contributing to both oncogene amplification and tumor heterogeneity. Here, we used Hi-C, super-resolution imaging, and long-read sequencing to explore the nuclear architecture of MYC -amplified ecDNA in colorectal cancer cells. Intriguingly, we observed frequent spatial proximity between ecDNA and 68 repetitive elements which we called ecDNA-interacting elements or EIEs. To characterize a potential regulatory role of EIEs, we focused on a fragment of the L1M4a1#LINE/L1 which we found to be co-amplified with MYC on ecDNA, gaining enhancer-associated chromatin marks in contrast to its normally silenced state. This EIE, in particular, existed as a naturally occurring structural variant upstream of MYC , gaining oncogenic potential in the transcriptionally permissive ecDNA environment. This EIE sequence is sufficient to enhance MYC expression and is required for cancer cell fitness. These findings suggest that silent repetitive genomic elements can be reactivated on ecDNA, leading to functional cooption and amplification. Repeat element activation on ecDNA represents a mechanism of accelerated evolution and tumor heterogeneity and may have diagnostic and therapeutic potential.

To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting that dispersed, nonrecurrent, noncoding mutations in cancer are functional. Overall, these data and interpretable gene regulatory models for cancer and healthy tissue provide a framework for understanding cancer-specific gene regulation.

Introduction: Currently, no quality-of-life instrument exists that captures the full experience of the mental health outlook (MHO), a coreHEM core outcome, in people with haemophilia, including the potential transformational experience of receiving gene therapy., Aim: To describe the methods used to develop a content validated patient-reported outcome measure (PROM) that measures MHO for people with haemophilia., Methods: A conceptual framework, developed from a literature/evidence review, was used to create an interview guide and draft a questionnaire. Males aged 15 or older with severe/moderate haemophilia were eligible to participate in concept elicitation or cognitive debriefing interviews. The conceptual framework was refined based on a thematic analysis of concept elicitation interviews and PROM items were developed from the conceptual framework. Cognitive debriefing sessions that prioritised relevance and understanding of the PROM were held in two rounds; items were updated iteratively., Results: A conceptual framework with five domains (stigma, anxiety, depression, life interference and identity) was constructed from over 300 identified MHO concepts. Fifty-three participants took part in interviews. After 32 concept elicitation interviews, the framework was updated by including eight new sub-concepts and eliminating two. Updates to the questionnaire included items added or removed and improved wording. The final coreHEM MHO PROM has 26 questions in two sections (general mental health associated with haemophilia, and a gene therapy section)., Conclusions: The instrument is content-validated and can be used as an exploratory outcome. MHO scores can be measured and compared to give more insight into patient quality of life., (© 2024 John Wiley & Sons Ltd.)

Purpose: The purpose of this study was to evaluate the benefits of a Bluetooth self-fitting device using an in situ hearing screening test and self-fitting processes., Method: Thirty Mandarin-speaking individuals (16 men and 14 women) with mild-to-moderate hearing loss participated in this study. The hearing screening test was conducted using neckband earphones of a Bluetooth self-fitting device controlled by a smartphone app. The hearing screening tests were compared with the pure-tone audiometry in an audiometric booth. The amplification benefits of the self-fitting program-aided condition were evaluated and compared with those of unaided and preset program-aided conditions using the Mandarin Hearing in Noise Test (MHINT) and questionnaires., Results: The pure-tone audiometry and hearing screening test results exhibited strong positive correlations at all test frequencies. In the environment with 90° noise, the sentence reception thresholds (SRTs) obtained for the self-fitting program-aided condition were significantly lower ( p = .032) than those obtained for the unaided condition, whereas no significant difference was observed between the preset program-aided and the unaided conditions. Moreover, the participants' satisfaction ratings for the devices were consistent with their MHINT results, with a strong positive correlation observed between satisfaction with self-fitting and user satisfaction in smartphone app's control, functionality, and learning. Younger participants were significantly more satisfied in learning to use the app., Conclusions: Bluetooth self-fitting devices can be used for simplified in situ hearing screenings with a sensitivity of 90.4%. The satisfaction ratings and improvements in SRTs indicate significant clinical benefits of the self-fitting program compared with the preset program, particularly in the 90°-noise environments.

FOXP3 is a lineage-defining transcription factor that controls differentiation and maintenance of suppressive function of regulatory T cells (Tregs). Foxp3 is exclusively expressed in Tregs in mice. However, in humans, FOXP3 is not only constitutively expressed in Tregs; it is also transiently expressed in stimulated CD4+CD25- conventional T cells (Tconvs) 1-3 . Mechanisms governing the expression of FOXP3 in human Tconvs are not understood. Here, we performed CRISPR interference (CRISPRi) screens using a 15K-member gRNA library tiling 39 kb downstream of the FOXP3 transcriptional start site (TSS) to 85 kb upstream of the TSS in Treg and Tconvs. The FOXP3 promoter and conserved non-coding sequences (CNS0, CNS1, CNS2 and CNS3), characterized as enhancer elements in murine Tregs, were required for maintenance of FOXP3 in human Tregs. In contrast, FOXP3 in human Tconvs depended on regulation at CNS0 and a novel Tconv-specific noncoding sequence (TcNS+) located upstream of CNS0. Arrayed validations of these sites identified an additional repressive cis-element overlapping with the PPP1R3F promoter (TcNS-). Pooled CRISPR knockouts revealed multiple transcription factors required for proper expression of FOXP3 in Tconvs, including GATA3, STAT5, IRF4, ETS1 and DNA methylation-associated regulators DNMT1 and MBD2. Analysis of ChIP-seq and ATAC-seq paired with knock-out (KO) of GATA3, STAT5, IRF4, and ETS1 revealed regulation of CNS0 and TcNS+ accessibility. Collectively, this work identified Treg-shared and Tconv-specific cis-elements and the trans-factors that interact with them, building a network of regulators controlling FOXP3 expression in human Tconvs., Competing Interests: Competing Interests Declaration A.M. is a cofounder of Site Tx, Arsenal Biosciences, Spotlight Therapeutics and Survey Genomics, serves on the boards of directors at Site Tx, Spotlight Therapeutics and Survey Genomics, is a member of the scientific advisory boards of Site Tx, Arsenal Biosciences, Cellanome, Spotlight Therapeutics, Survey Genomics, NewLimit, Amgen, and Tenaya, owns stock in Arsenal Biosciences, Site Tx, Cellanome, Spotlight Therapeutics, NewLimit, Survey Genomics, Tenaya and Lightcast and has received fees from Site Tx, Arsenal Biosciences, Cellanome, Spotlight Therapeutics, NewLimit, Gilead, Pfizer, 23andMe, PACT Pharma, Juno Therapeutics, Tenaya, Lightcast, Trizell, Vertex, Merck, Amgen, Genentech, GLG, ClearView Healthcare, AlphaSights, Rupert Case Management, Bernstein and ALDA. A.M. is an investor in and informal advisor to Offline Ventures and a client of EPIQ. The Marson laboratory has received research support from the Parker Institute for Cancer Immunotherapy, the Emerson Collective, Arc Institute, Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead and Anthem and reagents from Genscript and Illumina. C.T.M. is a Bio+Health Venture Fellow at Andreessen Horowitz. J.E.C. is a co-founder and SAB member of Serac Biosciences and an SAB member of Mission Therapeutics, Relation Therapeutics, Hornet Bio, and Kano Therapeutics. The lab of J.E.C. has funded collaborations with Allogene, Cimeio, and Serac. H.Y.C. is a cofounder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, and Orbital Therapeutics, and is an advisor of 10x Genomics, Arsenal Bio, Chroma Medicine, Exai Bio, and Spring Discovery.

Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death worldwide and in Taiwan. It is highly prevalent and has a tremendous impact on global health. Therefore, the Taiwan Society of Cardiology developed these best-evidence preventive guidelines for decision-making in clinical practice involving aspects of primordial prevention including national policies, promotion of health education, primary prevention of clinical risk factors, and management and control of clinical risk factors. These guidelines cover the full spectrum of ASCVD, including chronic coronary syndrome, acute coronary syndrome, cerebrovascular disease, peripheral artery disease, and aortic aneurysm. In order to enhance medical education and health promotion not only for physicians but also for the general public, we propose a slogan (2H2L) for the primary prevention of ASCVD on the basis of the essential role of healthy dietary pattern and lifestyles: " Healthy Diet and Healthy Lifestyles to Help Your Life and Save Your Lives ". We also propose an acronym of the modifiable risk factors/enhancers and relevant strategies to facilitate memory: " ABC 2 D 2 EFG-I'M 2 ACE" : Adiposity, Blood pressure, Cholesterol and Cigarette smoking, Diabetes mellitus and Dietary pattern, Exercise, Frailty, Gout/hyperuricemia, Inflammation/infection, Metabolic syndrome and Metabolic dysfunction-associated fatty liver disease, Atmosphere (environment), Chronic kidney disease, and Easy life (sleep well and no stress). Some imaging studies can be risk enhancers. Some risk factors/clinical conditions are deemed to be preventable, and healthy dietary pattern, physical activity, and body weight control remain the cornerstone of the preventive strategy., Competing Interests: Ting-Hsing Chao has been on the speaker bureau for Astrazeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Novartis, Pfizer, Sanofi, Tanabe, and TSH biopharm. All other authors report no potential conflicts of interest in relation to these guidelines.

Long-term exposure to ambient PM 2.5 is known associated with cardiovascular and respiratory health effects. However, the heterogeneous concentrationresponse function (CRF) between PM 2.5 exposure across different concentration range and cardiopulmonary disease and diabetes mellitus (DM) incidence, and their implications on attributable years lived with disability (YLD) and regulation policy has not been well-studied. In this retrospective longitudinal cohort study, disease-free participants (approximately 170,000 individuals, aged ≥ 30 years) from the MJ Health Database were followed up (2007-2017) regarding incidents of coronary heart disease (CHD), ischemic stroke, chronic obstructive pulmonary disease (COPD), lower respiratory tract infections (LRIs), and DM. We used a time-dependent nonlinear weight-transformation Cox regression model for the CRF with an address-matched 3-year mean PM 2.5 exposure estimate. Town/district-specific PM 2.5 -attributable YLD were calculated by multiplying the disease incidence rate, population attributable fraction, disability weight, and sex-age group specific subpopulation for each disease separately. The estimated CRFs for cardiopulmonary diseases were heterogeneously with the hazard ratios (HRs) increased rapidly for CHD and ischemic stroke at PM 2.5 concentration lower than 10 μg/m 3 , whereas the HRs for DM (LRIs) increased with PM 2.5 higher than 15 (20) μg/m 3 . Women had higher HRs for ischemic stroke and DM but not CHD. Relative to the lowest observed PM 2.5 concentration of 6 μg/m 3 of the study population, the PM 2.5 level with an extra risk of 0.1 % (comparable to the disease incidence) for CHD, ischemic stroke, DM, and LRIs were 8.59, 11.85, 22.09, and 24.23 μg/m 3 , respectively. The associated attributable YLD decreased by 51.4 % with LRIs reduced most (83.6 %), followed by DM (63.7 %) as a result of PM 2.5 concentration reduction from 26.10 to 16.82 μg/m 3 during 2011-2019 in Taiwan. The proportion of YLD due to CHD and ischemic stroke remained dominant (56.4 %-69.9 %). The cost-benefit analysis for the tradeoff between avoidable YLD and mitigation cost suggested an optimal PM 2.5 exposure level at 12 μg/m 3 . CRFs for cardiopulmonary diseases, attributable YLD, and regulation level, may vary depending on the national/regional background and spatial distribution of PM 2.5 concentrations, as well as demographic characteristics., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chu-Chih Chen reports financial support was provided by National Science and Technology Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The coronavirus disease (COVID-19) pandemic broke out in March 2020, causing tremendous damage to public health and more than 6 million deaths. After authorization for the emergency use of COVID-19 vaccines, various adverse events have been reported, including optic neuritis. COVID-19 vaccination was implemented in Taiwan in March 2021., Methods: We report patients who developed optic neuritis after COVID-19 vaccination at one university-affiliated tertiary hospital, between March 2021 and December 2022. We also provided a literature review of optic neuritis cases after COVID-19 vaccination., Results: Five patients who developed optic neuritis after COVID-19 vaccination have been identified. Four brands of vaccine used were as follows: Moderna, Pfizer-BioNTech, Medigen, and Oxford AstraZeneca. Optic neuritis developed after the first dose of vaccination in 4 patients, whereas in 1 patient, it developed after the second shot. In the 3 patients with poor initial visual acuity, intravenous methylprednisolone pulse therapy achieved substantial improvement., Conclusions: Optic neuritis is a rare but potentially vision-threatening adverse effect of COVID-19 vaccination. We suggest early diagnosis and treatment to maximize visual outcomes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by North American Neuro-Ophthalmology Society.)

Patients may find it challenging to accept several FDA-approved drugs for Alzheimer's disease (AD) treatment due to their unaffordable prices and side effects. Despite the known antioxidant, anti-inflammatory, and microbiota-regulating effects of common buckwheat (Fagopyrum esculentum) polysaccharides (FEP), their specific role in preventing AD has not been determined. Here, this study investigated the preventive effects of FEP on AD development in AlCl 3 -treated rats. The physical properties of FEP were evaluated using X-ray diffraction, FTIR, TGA, DSC, monosaccharide composition, molecular weight, and scanning electron microscopy. The results demonstrated that FEP administration improved memory and learning ability in AlCl 3 -treated rats. Additionally, AD pathological biomarkers (APP, BACE1, Aβ 1 - 42 , and p-Tau Ser404 ), inflammatory-associated proteins (IL-1β, IL-6, TNF-α, and Iba1), and MDA and the RAGE/p38/NF-κB pathway were elevated in AlCl 3 -treated rats. Moreover, these effects were reversed by the upregulation of LRP1, anti-inflammatory cytokines (IL-4 and IL-10), antioxidant enzymes (SOD and catalase), and autophagy proteins (Atg5, Beclin-1, and LC3B). Furthermore, FEP treatment increased the levels of short-chain fatty acids (SCFAs) and the abundance of SCFAs-producing microbes ([Eubacterium]&#95;xylanophilum&#95;group, Lachnospiraceae&#95;NK4A136&#95;group, Lactobacillus). Overall, FEP mitigated oxidative stress, RAGE/p38/NF-κB-mediated neuroinflammation, and AD-associated proteins by upregulating autophagy and SCFA levels, which led to the amelioration of cognitive impairment through microbiota-gut-brain communication in AlCl 3 -treated rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: This study examined the psychometric properties and measurement invariance of the 10-item Awareness of Age-Related Change Short Form (AARC-SF) questionnaire in a Chinese-speaking sample of older adults in Taiwan., Research Design and Methods: Data from 292 participants (Mage = 77.64 years) in the Healthy Aging Longitudinal Study in Taiwan cohort were used for Study 1, whereas data from young-old adult samples in Germany were used for Study 2., Results: Study 1 showed that the AARC-SF had satisfactory reliability and validity for assessing adults' AARC in Taiwan. Analyses confirmed the 2-factor structure of AARC-gains and AARC-losses. Study 2 demonstrated strong measurement invariance across men and women, whereas direct comparisons of the item scores between young-old adults and old-old adults need to be made with caution. Noninvariance of loadings indicated that certain items were more closely linked to AARC-gains and AARC-losses in Taiwan than in Germany. Noninvariance of intercepts suggested potential biases in comparing item scores between Taiwanese and German older adults., Discussion and Implications: The AARC-SF emerged as a reliable and valid instrument for capturing positive and negative subjective aging experiences among Taiwanese older adults. However, it is noteworthy that some items on the AARC-SF may solicit different responses from individuals of different ages and different countries of origin, requiring caution with age group and cross-cultural comparisons., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Introduction: This study aimed to investigate the prevalence of different forms of harm from others' drinking (HFOD), predictors and the relationship with multi-dimensional quality of life among young adults in an emerging alcohol market in Asia-Taiwan., Methods: Data were extracted from a 2018 household survey with national representativeness on substance use experiences. The analytic sample comprised 4901 participants aged 18-34. Eight items were used to measure HFOD experiences. Five-dimensional quality of life was assessed by the EQ-5D-5L. Multivariable regressions with complex survey analyses were performed to estimate the prevalence and risk association., Results: Almost 4.2% of young adults experienced any form of HFOD; psychological harm occurred more prevalently than physical harm (3.7% and 1.5%, respectively). Those aged 25-29 and 30-34 had a two- to three-fold risk of HFOD compared with those aged 18-24. Both non-drunk drinking and drunk drinking were associated with an increased risk of psychological HFOD (adjusted odds ratio 2.36 and 5.89, respectively), whereas the risk of physical HFOD was related only to drunk drinking (adjusted odds ratio 7.8). Psychological HFOD victimisation emerged as the strongest predictor for deteriorated quality of life (adjusted b -0.14; 95% confidence interval -0.24, -0.04), especially in the dimensions of pain/discomfort and anxiety/depression. Among HFOD victims, only 33% sought help., Discussion and Conclusions: The HFOD among young adults, commonly exhibited in psychological form, was linked with deteriorated quality of life; nonetheless, young HFOD victims are under-recognised. When devising interventions for alcohol harm, developmental perspectives should be integrated into policies implemented in healthcare and community settings., (© 2024 Australasian Professional Society on Alcohol and other Drugs.)

Dietary patterns related to inflammation have garnered great interest in disease prevention. The aims of this study were to evaluate whether a proinflammatory diet affects the incidence of frailty and its reversal in a prospective follow-up study. Data were taken from 5663 community-dwelling individuals ≥ 55 years old in Taiwan. The energy-adjusted dietary inflammatory index (DII) and the Empirical Dietary Inflammatory Patterns-Healthy Aging Longitudinal Study in Taiwan (EDIP-HALT) at baseline were calculated using a food frequency questionnaire. Frailty was assessed with Fried's criteria in 2008-2013 and 2013-2020. Associations with changes in frailty status were assessed with multinominal logistic regressions and adjusted for major confounders. Higher EDIP-HALST scores (proinflammatory) were associated with higher odds of frailty among baseline robust participants in men (OR = 2.44, 95% CI = 1.42-4.21, p- trend < 0.01) and broadline associated in women (OR = 1.96, 95% CI = 0.96-3.98, p- trend = 0.05), but associated with lower odds of reversing back to robust among baseline prefrail participants. However, the later association was only observed in women, and the relationships were stronger in the middle tertile (second vs. first tertile, OR = 0.40, 95% CI = 0.25-0.65). A pro-inflammatory diet pattern was associated with higher odds of frailty onset in baseline robust participants and lower odds of reversal in baseline prefrail female participants.

Background: Cardiac blood cysts are exceedingly rare cardiac tumours usually found on cardiac valves in infants. We report and discuss a rare unique case wherein a giant atrial septal cardiac blood cyst was found in an adult., Case Summary: A 59-year-old Chinese lady with history of hypertension, hyperlipidemia and transient ischaemic attack presented with atypical chest pain. Her ECG suggested right ventricular strain. Echocardiography revealed a large right atrial intracardiac mass attached to the interatrial septum which prolapsed into the right ventricle during each cardiac cycle with associated dilatation of the right atrium and right ventricle. Computed tomography scans showed no evidence of malignancy or metastasis. Considering our patient's profile and the characteristics of the mass, it was opined to likely be a cardiac myxoma. After consultation with our cardiothoracic surgeons, she underwent surgical resection of the intracardiac mass. Histology revealed that the intracardiac mass was a cardiac blood cyst., Discussion: First described by Elsasser in 1844, cardiac blood cysts are extremely rare benign cardiac tumours very rarely seen in adults. Though benign, they have been associated with outflow tract obstruction, valvular regurgitation and embolization. Symptomatic patients do well with surgical resection, while long-term outcomes in asymptomatic patients followed up with serial echocardiograms are mixed. Due to its rarity, existing literature is limited to case reports and small case series, with a lack of guidelines on management till recently. Our case report serves to highlight this unique presentation of an exceedingly rare intracardiac tumour., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/I82).

Oncogene amplification on extrachromosomal DNA (ecDNA) is a pervasive driver event in cancer, yet our understanding of how ecDNA forms is limited. Here, we couple a CRISPR-based method for ecDNA induction with extensive characterization of newly formed ecDNA to examine their biogenesis. We find that DNA circularization is efficient, irrespective of 3D genome context, with formation of 800kb, 1 Mb, and 1.8 Mb ecDNAs reaching or exceeding 15%. We show non-homologous end joining and microhomology-mediated end joining both contribute to ecDNA formation, while inhibition of DNA-PKcs and ATM have opposing impacts on ecDNA formation. EcDNA and the corresponding chromosomal excision scar can form at significantly different rates and respond differently to DNA-PKcs and ATM inhibition. Taken together, our results support a model of ecDNA formation in which double strand break ends dissociate from their legitimate ligation partners prior to joining of illegitimate ends to form the ecDNA and excision scar.

Nanoparticle-mediated photoporation has arisen as a universal intracellular delivery tool; however, the direct interaction of nanoparticles and cells hampers its clinical translation. Here, we report a uniform contactless intracellular delivery that transfects a large number of cells within a minute and avoids direct contact of nanoparticles and cells, thereby improving the cell viability. Our platform consists of an array of polydimethylsiloxane (PDMS) mixed reduced graphene oxide (rGO) nanoflakes on pyramidal microtips, uniformly distributed at the apex of the tip. The extraordinary optoelectronic properties of rGO were combined with micro-pyramidal cavities to entrap light in micro-cavities and efficiently convert it into heat through multiple reflections and absorptions. As a result, ultralow infra-red laser pulse irradiation could create cavitation bubbles followed by cell membrane deformation and biomolecular delivery. Using this delivery platform, we have achieved the delivery of small to large cargo (668 Da to 465 kDa) in various mammalian cells, including hard-to-transfect H9C2 cardiomyocytes. The best results were achieved for enzyme (465 kDa) delivery with a transfection efficiency and cell viability of 95% and 98%, respectively, in SiHa cells. The highly efficient cargo delivery tool demonstrated a safe and effective approach for cell therapy and diagnostics.

In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury 1-4 . Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8 + T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)