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Background: Real-world vaccine effectiveness following the third dose of vaccination against SARS-CoV-2 remains less investigated among people with HIV (PWH)., Methods: PWH receiving the third dose of BNT162b2 and mRNA-1273 (either 50- or 100-μg) were enrolled. Participants were followed for 180 days until the fourth dose of COVID-19 vaccination, SARS-CoV-2 infection, seroconversion of anti-nucleocapsid IgG, death, or loss to follow-up. Anti-spike IgG was determined every 1-3 months., Results: Of 1427 participants undergoing the third-dose COVID-19 vaccination, 632 (44.3%) received 100-μg mRNA-1273, 467 (32.8%) 50-μg mRNA-1273, and 328 (23.0%) BNT162b2 vaccine and the respective rate of SARS-CoV-2 infection or seroconversion of anti-nucleocapsid IgG was 246.1, 280.8 and 245.2 per 1000 person-months of follow-up (log-rank test, p = 0.28). Factors associated with achieving anti-S IgG titers >1047 BAU/mL included CD4 count <200 cells/mm 3 (adjusted odds ratio [aOR], 0.11; 95% CI, 0.04-0.31), plasma HIV RNA >200 copies/mL (aOR, 0.27; 95% CI, 0.09-0.80), having achieved anti-spike IgG >141 BAU/mL within 3 months after primary vaccination (aOR, 3.69; 95% CI, 2.68-5.07), receiving BNT162b2 vaccine as the third dose (aOR, 0.20; 95% CI, 0.10-0.41; reference, 100-μg mRNA-1273), and having previously received two doses of mRNA vaccine in primary vaccination (aOR, 2.46; 95% CI, 1,75-3.45; reference, no exposure to mRNA vaccine)., Conclusions: PWH receiving different types of the third dose of COVID-19 vaccine showed similar vaccine effectiveness against SARS-CoV-2 infection. An additional dose with 100-μg mRNA-1273 could generate a higher antibody response than with 50-μg mRNA-1273 and BNT162b2 vaccine., 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. Published by Elsevier B.V.)

The contrast between the disruption of genome topology after cohesin loss and the lack of downstream gene expression changes instigates intense debates regarding the structure-function relationship between genome and gene regulation. Here, by analyzing transcriptome and chromatin accessibility at the single-cell level, we discover that, instead of dictating population-wide gene expression levels, cohesin supplies a general function to neutralize stochastic coexpression tendencies of cis-linked genes in single cells. Notably, cohesin loss induces widespread gene coactivation and chromatin co-opening tens of million bases apart in cis. Spatial genome and protein imaging reveals that cohesin prevents gene co-bursting along the chromosome and blocks spatial mixing of transcriptional hubs. Single-molecule imaging shows that cohesin confines the exploration of diverse enhancer and core promoter binding transcriptional regulators. Together, these results support that cohesin arranges nuclear topology to control gene coexpression in single cells., (© 2024. The Author(s).)

Abstract: Chen, P-T, Lin, Y-C, Chang, H-Y, Chiu, C-H, Chen, C-Y, Chen, P, and Lin, Y-H. Effects of shoulder corrective training program on pitching loads and sonographic morphology in elbow joint in youth baseball players. J Strength Cond Res 38(8): e440-e447, 2024-We assessed the effects of a 12-week shoulder corrective training program for shoulder flexibility and strengthening on pitching loads and sonographic morphology of the elbow joints in youth baseball players. Seventeen subjects were recruited and underwent evaluations before and after the training program. We found that following training, subjects demonstrated significantly increased ranges of shoulder internal rotation (38.9 ± 12.9° vs. 69.2 ± 10.8°, p < 0.001), external rotation (91.2 ± 14.6° vs. 107.3 ± 9.5°, p = 0.004), and horizontal adduction (21.5 ± 8.0° vs. 32.7 ± 7.3°, p = 0.002); improved strength in the shoulder internal rotators (8.7 ± 1.6 kg vs. 9.8 ± 2.1 kg, p = 0.04), external rotators (6.5 ± 1.9 kg vs. 7.5 ± 2.8 kg, p = 0.04), middle trapezius (12.7 ± 2.1 kg vs. 14.3 ± 2.4 kg, p = 0.04), and middle deltoid muscles (10.8 ± 3.3 kg vs. 14.8 ± 3.2 kg, p = 0.001); and decreased thickness of the ulnar collateral ligament (6.1 ± 0.6 mm vs. 4.8 ± 0.7 mm, p = 0.002). Although there was no substantial change in elbow torque and arm speed, significantly increased ball speed (51.2 ± 4.6 mph vs. 54.1 ± 4.5 mph, p < 0.001) and decreased arm slot (63.8 ± 11.9° vs. 53.0 ± 12.7°, p = 0.02) were observed. We suggest that adequate corrective training should be performed regularly to minimize or mitigate adverse soft tissue changes at the elbow in youth baseball players. Balanced shoulder strength and flexibility may decrease medial elbow stress during pitching. Future studies should consider the kinetic and kinematic effects of other corrective training programs on the shoulder or elbow joint during pitching., (Copyright © 2024 National Strength and Conditioning Association.)

Telomerase is intimately associated with stem cells and cancer, because it catalytically elongates telomeres-nucleoprotein caps that protect chromosome ends 1 . Overexpression of telomerase reverse transcriptase (TERT) enhances the proliferation of cells in a telomere-independent manner 2-8 , but so far, loss-of-function studies have provided no evidence that TERT has a direct role in stem cell function. In many tissues, homeostasis is shaped by stem cell competition, a process in which stem cells compete on the basis of inherent fitness. Here we show that conditional deletion of Tert in the spermatogonial stem cell (SSC)-containing population in mice markedly impairs competitive clone formation. Using lineage tracing from the Tert locus, we find that TERT-expressing SSCs yield long-lived clones, but that clonal inactivation of TERT promotes stem cell differentiation and a genome-wide reduction in open chromatin. This role for TERT in competitive clone formation occurs independently of both its reverse transcriptase activity and the canonical telomerase complex. Inactivation of TERT causes reduced activity of the MYC oncogene, and transgenic expression of MYC in the TERT-deleted pool of SSCs efficiently rescues clone formation. Together, these data reveal a catalytic-activity-independent requirement for TERT in enhancing stem cell competition, uncover a genetic connection between TERT and MYC and suggest that a selective advantage for stem cells with high levels of TERT contributes to telomere elongation in the male germline during homeostasis and ageing., (© 2024. The Author(s).)

The therapeutic efficacy of immunotherapy is limited in the majority of colorectal cancer patients due to the low mutational and neoantigen burdens in this immunogenically "cold" microsatellite stability-colorectal cancer (MSS-CRC) cohort. Here, we showed that DNA methyltransferase (DNMT) inhibition upregulated neoantigen-bearing gene expression in MSS-CRC, resulting in increased neoantigen presentation by MHC class I in tumor cells and leading to increased neoantigen-specific T-cell activation in combination with radiotherapy. The cytotoxicity of neoantigen-reactive T cells (NRTs) to DNMTi-treated cancer cells was highly cytotoxic, and these cells secreted high IFNγ levels targeting MSS-CRC cells after ex vivo expansion of NRTs with DNMTi-treated tumor antigens. Moreover, the therapeutic efficacy of NRTs further increased when NRTs were combined with radiotherapy in vivo. Administration of DNMTi-augmented NRTs and radiotherapy achieved an ∼50 % complete response and extended survival time in an immunocompetent MSS-CRC animal model. Moreover, remarkably, splenocytes from these mice exhibited neoantigen-specific T-cell responses, indicating that radiotherapy in combination with DNMTi-augmented NRTs prolonged and increased neoantigen-specific T-cell toxicity in MSS-CRC patients. In addition, these DNMTi-augmented NRTs markedly increase the therapeutic efficacy of cancer vaccines and immune checkpoint inhibitors (ICIs). These data suggest that a combination of radiotherapy and epi-immunotherapeutic agents improves the function of ex vivo-expanded neoantigen-reactive T cells and increases the tumor-specific cytotoxic effector population to enhance therapeutic efficacy in MSS-CRC., 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The benefits of rapidly up-titrating evidence-based treatments following heart failure (HF) hospitalizations were demonstrated in the The Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies (STRONG-HF) trial and emphasized in contemporary HF guidelines. We aimed to assess up-titration patterns of guideline-directed medical treatments in the Taiwanese HF population. Combining data from the Taiwan Society of Cardiology - Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry and the Treatment with Angiotensin Receptor neprilysin inhibitor for Taiwan Acute Heart Failure (TAROT-AHF) study cohort, we formed the "Taiwan real-world cohort". We compared these data with subgroups of patients with left ventricular ejection fraction ≤40% in the STRONG-HF trial. Patients in the Taiwan cohort exhibited similar blood pressure, heart rate and N-terminal pro B-type natriuretic peptide levels at discharge compared with those in the STRONG-HF trial. A higher proportion of patients in the STRONG-HF high-intensity care group received up-titrations compared with those in the usual care group and the Taiwan cohort. Composite all-cause mortality or HF hospitalization at 180 days for patients in the high-intensity care group, usual care group, and Taiwan cohort were 17.4%, 23.7%, and 31.9%, respectively, with differences largely contributed by HF hospitalization (10.1%, 17.9%, and 27.6%, respectively), whereas all-cause mortality rates were similar (11.0%, 9.6%, and 9.3%, respectively). Gender did not affect this trend. In conclusion, our data highlights a treatment gap between the STRONG-HF trial and real-world practices in Taiwan, urging prompt optimization of HF therapy., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Fine particulate matter (PM 2.5 ) is a common major air pollutant associated with decreased lung function, induced allergic airway inflammation closely correlated with chronic lung diseases. Angiopoietin-like protein 4 (ANGPTL4) is a cytokine with multiple functions, participating in processes such as inflammation, angiogenesis, and metastasis. Curcumin is an active compound found in turmeric plants and possesses various pharmacological effects, including antioxidant, anti-inflammatory, anticancer, and immunomodulatory properties. The aim of this study was twofold: firstly, to investigate the involvement of ANGPTL4 in lung inflammation and carcinogenesis under PM 2.5 exposure, and secondly, to explore the impact of curcumin on ANGPTL4 expression and its potential in lung cancer chemoprevention. We used protein array to detect several proinflammatory cytokines and then used qPCR to confirm by increasing the concentration of PM 2.5 to enhance the expressions of CXCL1, CXCL5; IL-1α, IL-1β, MIP-3α and inflammation- or fibrosis-associated proteins. Curcumin inhibits PM 2.5 - induced ANGPTL4 and the IκB-α (inhibitor of NFκB)-dependent inflammatory pathway. Silencing ANGPTL4 by shRNA restore IκB-α and MIP-3α expression. In conclusion, the increased expression of ANGPTL4 after treatment with PM 2.5 in lung cells may be one of the mechanisms by which PM 2.5 exposure contributes to lung inflammation progression. Our results provide evidence that curcumin in anti-inflammation therapeutics could serve as a beneficial chemopreventive agent., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jiunn-Liang Ko reports financial support was provided by National Science and Technology Council, Taiwan. Ko-Huang Lue reports financial support was provided by Chung Shan Medical University Hospital. 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. Published by Elsevier B.V.)

Autophagy can be classified as degradative and secretory based on distinct functions. The small GTPase proteins Rab8a and Rab37 are responsible for secretory autophagy-mediated exocytosis of IL-1β, insulin, and TIMP1 (tissue inhibitor of 54 metalloproteinase 1). Other Rab family members participating in secretory autophagy are poorly understood. Herein, we identified 26 overlapped Rab proteins in purified autophagosomes of mouse pancreatic β-cell "Min-6" and human lung cancer cell "CL1-5-Q89L" with high secretory autophagy tendency by LC-MS/MS proteomics analysis. Six Rab proteins (Rab8a, Rab11b, Rab27a, Rab35, Rab37, and Rab7a) were detected in autophagosomes of four cell lines, associating them with autophagy-related vesicle trafficking. We used CL1-5-Q89L cell line model to evaluate the levels of Rab proteins colocalization with autophagy LC3 proteins and presence in purified autophagosomes. We found five Rab proteins (Rab8a, Rab11b, Rab27a, Rab35, and Rab37) are highly expressed in the autophagosome compared to the normal control by immunoblotting under active secretion conditions. However, only Rab8a, Rab35, and Rab37 showing high colocalization with LC3 protein by cofocal microscopy. Despite the discrepancy between the image and immunoblotting analysis, our data sustains the speculation that Rab8a, Rab11b, Rab27a, Rab35, and Rab37 are possibly associated with the secretory autophagy machinery. In contrast, Rab7a shows low colocalization with LC3 puncta and low level in the autophagosome, suggesting it regulates different vesicle trafficking machineries. Our findings open a new direction toward exploring the role of Rab proteins in secretory autophagy-related cargo exocytosis and identifying the cargoes and effectors regulated by specific Rab proteins., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background: Sodium-glucose cotransporter-2 inhibitors, such as empagliflozin, are pivotal therapies for heart failure. However, the effect of empagliflozin on doxorubicin-related cardiac dysfunction remains unclear., Methods: Human induced pluripotent stem cell- and embryonic stem cell-derived cardiomyocytes were used to investigate the direct effect of empagliflozin on human cardiomyocytes. Then, the c-Jun amino-terminal kinases (JNK) inhibitor SP600125 was administered to the doxorubicin cardiotoxicity model in vitro and in vivo to investigate the role of JNK in empagliflozin., Results: In human stem cell-derived cardiomyocytes, pretreatment with empagliflozin attenuated doxorubicin-induced cleavage of caspase 3 and other apoptosis markers. Empagliflozin significantly attenuated doxorubicin-induced phosphorylation of JNK and p38. Inhibiting the phosphorylation of JNK (SP600125) or STAT3 attenuated doxorubicin-induced apoptosis, but inhibiting the phosphorylation of p38 did not. SP600125 inhibits the phosphorylation of STAT3 (S727), and a STAT3 (Y705) inhibitor also inhibits the phosphorylation of JNK. Empagliflozin and SP600125 attenuated doxorubicin-induced increases in reactive oxygen species (ROS) and decreases in oxidized nicotinamide adenine dinucleotide (NAD + ). In animal studies, empagliflozin and SP600125 attenuated doxorubicin-induced cardiac dysfunction and fibrosis., Conclusions: Empagliflozin attenuated doxorubicin-induced apoptosis by inhibiting the phosphorylation of JNK and its downstream signaling pathways, including ROS and NAD+., 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Autophagy is a self-recycling machinery to maintain cellular homeostasis by degrading harmful materials in the cell. Autophagy-related gene 5 (Atg5) is required for autophagosome maturation. However, the role of Atg5 in tumorigenesis under autophagy deficient conditions remains unclear. This study focused on the autophagy-independent role of Atg5 and the underlying mechanism in tumorigenesis. We demonstrated that knockout of autophagy-related genes including Atg5, Atg7, Atg9, and p62 in mouse embryonic fibroblast (MEF) cells consistently decreased cell proliferation and motility, implying that autophagy is required to maintain diverse cellular functions. An Atg7 knockout MEF (Atg7 -/- MEF) cell line representing deprivation of autophagy function was used to clarify the role of Atg5 transgene in tumorigenesis. We found that Atg5-overexpressed Atg7 -/- MEF (clone A) showed increased cell proliferation, colony formation, and migration under autophagy deficient conditions. Accordingly, rescuing the autophagy deficiency of clone A by overexpression of Atg7 gene shifts the role of Atg5 from pro-tumor to anti-tumor status, indicating the dual role of Atg5 in tumorigenesis. Notably, the xenograft mouse model showed that clone A of Atg5-overexpressed Atg7 -/- MEF cells induced temporal tumor formation, but could not prolong further tumor growth. Finally, biomechanical analysis disclosed increased Wnt5a secretion and p-JNK expression along with decreased β-catenin expression. In summary, Atg5 functions as a tumor suppressor to protect the cell under normal conditions. In contrast, Atg5 shifts to a pro-tumor status under autophagy deprivation conditions., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Objectives: This study examined the associations between pulse pressure, hypertension, and the decline in physical function in a prospective framework., Study Design: The Healthy Aging Longitudinal Study tracked a group of Taiwanese adults aged 55 or more over an average of 6.19 years to assess pulse pressure and decline in physical function, including in handgrip strength, gait speed, and 6-min walking distance, at baseline (2009-2013) and in the second phase of assessments (2013-2020)., Main Outcome Measures: Pulse pressure was calculated as the difference between systolic and diastolic blood pressure values. Weakness, slowness, and low endurance were defined as decreases of ≥0.23 m/s (one standard deviation) in gait speed, ≥5.08 kg in handgrip strength, and ≥ 57.73 m in a 6-min walk, as determined from baseline to the second phase of assessment. Linear and logistic regressions were employed to evaluate the associations between pulse pressure, hypertension, and decline in physical function., Results: Baseline pulse pressure was associated with future handgrip strength (beta = -0.017, p = 0.0362), gait speed (beta = -0.001, p < 0.0001), and 6-min walking distance (beta = -0.470, p < 0001). In multivariable models, only handgrip strength (beta = -0.016, p = 0.0135) and walking speed (beta = -0.001, p = 0.0042) remained significantly associated with future pulse pressure. Older adults with high systolic blood pressure (≥140 mmHg) and elevated pulse pressure (≥60 mmHg) exhibited a significantly increased risk of weakness (odds ratio: 1.30, 95 % confidence interval: 1.08-1.58), slowness (1.29, 1.04-1.59), and diminished endurance (1.25, 1.04-1.50) compared with the reference group, who exhibited systolic blood pressure of <140 mmHg and pulse pressure of <60 mmHg., Conclusions: Among older adults, pulse pressure is associated with a decline in physical function, especially in terms of strength and locomotion., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Probability discounting (PD), which refers to the process of adjusting the value of future probabilities when making decisions, is a method of measuring impulsive decision-making; however, the relationship between PD and nicotine remains unclear. The current study aimed at investigating the significance of PD in individuals who smoke., Methods: According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched the PubMed, Embase, PsycINFO, and Web of Science databases for articles comparing individuals who smoke and their tobacco-naïve controls using PD task as outcome measure from inception to May 2023. The main outcome was an overall difference in PD function, while subgroup analysis and meta-regression were conducted to examine the analysis methods and the moderators of PD., Results: Fourteen studies in total involving 384 individuals who smoke and 493 controls (mean age = 24.32 years, range = 15.1-38.05 years) were analyzed. The effect of smoking on PD was significant (g = 0.51, p = .02). The discounting parameter from the equation, compared to the area under the curve, was more sensitive to estimating PD function (p = .01). Regression analysis showed positive correlations of PD with female percentage, age, and the number of probability options (all p < .04), but not with the number of choices at each probability and maximum reward magnitude (all p > .07). There was no significant publication bias across the eligible studies (p = .09)., Conclusion and Scientific Significance: Our findings, which are the first to demonstrate a smaller PD (i.e., prone to risk-taking) in individuals who smoke, shed light on the appropriate analysis method, gender effect, age, and probability options on the PD function., (© 2024 The American Academy of Addiction Psychiatry (AAAP).)

Late chronotype during adolescence is a critical risk factor for poor physical and mental health among adolescents. While social loneliness is confirmed to negatively influence sleep behaviors, the long-term effect of social loneliness on chronotype remains unknown. This study aims to investigate whether social loneliness trajectories from middle childhood to adolescence are associated with chronotype in late adolescence and examine the potential sex differences in these associations. Data were obtained from 2398 adolescents who participated in the Child and Adolescent Behaviors in Long-Term Evolution project. Chronotype was calculated as the midpoint of sleep on free days adjusted for sleep debt. Group-based trajectory modeling and multiple linear regression were employed to establish social loneliness trajectories and determine their associations with chronotype. Social loneliness trajectories were significantly associated with chronotype and varied by sex. Specifically, boys following a high-decreasing trajectory had earlier chronotype during late adolescence than did those following a low-decreasing trajectory (B =  - 0.07; p < 0.05). By contrast, girls following a low-to-moderate-increasing trajectory exhibited later chronotype than did those following a low-stable trajectory (B = 0.07; p < 0.01). Social loneliness trajectories, especially those displaying significant fluctuations over time, are critical indicators influencing chronotype among adolescents. Furthermore, these trajectories and their associations with chronotype display sex differences. These findings highlight the need for early interventions for psychological factors such as social loneliness to ensure that the late chronotype can be prevented. In addition, sex variations must be considered., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Iron deficiency (ID) is a common comorbidity among patients with heart failure and reduced ejection fraction (HFrEF), and is associated with poorer outcomes independent of anemia. This study aimed to evaluate the prevalence and prognostic significance of ID in Taiwanese patients with HFrEF., Methods: We included HFrEF patients from two multicenter cohorts at different periods. The multivariate Cox regression analysis was applied to assess the risk of outcomes associated with ID, accounting for the varying risk of death., Results: Of the 3612 patients with HFrEF registered from 2013 to 2018, 665 patients (18.4%) had available baseline iron profile measurements. Of these, 290 patients (43.6%) were iron deficient; 20.2% had ID+/anemia+, 23.4% ID+/anemia-, 21.5% ID-/anemia+, and 34.9% ID-/anemia-. Regardless of anemia status, patients with coexisting ID had a higher risk than those without ID (all-cause mortality: 14.3 vs 9.5 per 100 patient-years, adjusted hazard ratio [HR] 1.33; 95% confidence interval [CI], 0.96-1.85; p = 0.091; cardiovascular mortality: 10.5 per 100 patient-years vs 6.1, adjusted HR 1.54 [95% CI, 1.03-2.30; p = 0.037]; cardiovascular mortality or first unplanned hospitalization for HF: 36.7 vs 19.7 per 100 patient-years, adjusted HR 1.57 [95% CI, 1.22-2.01; p < 0.001]). Among patients eligible for treatment in the IRONMAN trial design (43.9%), parenteral iron therapy was estimated to reduce heart failure hospitalizations and cardiovascular deaths by 13.7 per 100 patient-years., Conclusion: Iron profiles were tested in less than one-fifth of the Taiwanese HFrEF cohort. ID was present in 43.6% of tested patients and was independently associated with poor prognosis in these patients., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Text-mining algorithms can identify the most prevalent factors of risk-benefit assessment on the use of complementary and integrative health approaches that are found in healthcare professionals' written notes. The aims of this study were to discover the key factors of decision-making on patients' complementary and integrative health use by healthcare professionals and to build a consensus-derived decision algorithm on the benefit-risk assessment of complementary and integrative health use in diabetes. The retrospective study of an archival dataset used a text-mining method designed to extract and analyze unstructured textual data from healthcare professionals' responses. The techniques of classification, clustering, and extraction were performed with 1398 unstructured clinical notes made by healthcare professionals between 2019 and 2020. The most important factor for decision-making by healthcare professionals about complementary and integrative health use in patients with diabetes was the ingredients of the product. Other important factors were the patient's diabetes control, the undesirable effects from complementary and integrative health, evidence-based complementary and integrative health, medical laboratory data, and the product's affordability. This exploratory text-mining study provides insight into how healthcare professionals decide complementary and integrative health use for patients with diabetes after a risk-benefit assessment from clinical narrative notes., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

The transcription factor PsrA regulates fatty acid metabolism, the type III secretion system, and quinolone signaling quorum sensing system in Pseudomonas aeruginosa . To explore additional roles of PsrA in P. aeruginosa , this study engineered a P. aeruginosa PAO1 strain to carry a recombinant plasmid with the psrA gene (pMMB psrA ) and examined the impact of elevated psrA expression to the bacterium. Transcriptomic analysis revealed that PsrA significantly downregulated genes encoding the master quorum-sensing regulators, RhlR and LasR, and influenced many quorum-sensing-associated genes. The role of PsrA in quorum sensing was further corroborated by testing autoinducer synthesis in PAO1 [pMMB psrA ] using two reporter bacteria strains Chromobacterium violaceum CV026 and Escherichia coli [pSB1075], which respond to short- and long-chain acyl homoserine lactones, respectively. Phenotypic comparisons of isogenic Δ psrA , Δ lasR , and Δ psrA Δ lasR mutants revealed that the reduced elastase, caseinase, and swarming activity in PAO1 [pMMB psrA ] were likely mediated through LasR. Additionally, electrophoretic mobility shift assays demonstrated that recombinant PsrA could bind to the lasR promoter at a 5'-AAACGTTTGCTT-3' sequence, which displays moderate similarity to the previously reported consensus PsrA binding motif. Furthermore, the PsrA effector molecule oleic acid inhibited PsrA binding to the lasR promoter and restored several quorum sensing-related phenotypes to wild-type levels. These findings suggest that PsrA regulates certain quorum-sensing phenotypes by negatively regulating lasR expression, with oleic acid acting as a crucial signaling molecule., 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., (Copyright © 2024 Kok, Tsai, Liao, Lo, Cheng, Lin and Chang.)

Extrachromosomal DNA is a common cause of oncogene amplification in cancer. The non-chromosomal inheritance of ecDNA enables tumors to rapidly evolve, contributing to treatment resistance and poor outcome for patients. The transcriptional context in which ecDNAs arise and progress, including chromosomally-driven transcription, is incompletely understood. We examined gene expression patterns of 870 tumors of varied histological types, to identify transcriptional correlates of ecDNA. Here, we show that ecDNA-containing tumors impact four major biological processes. Specifically, ecDNA-containing tumors up-regulate DNA damage and repair, cell cycle control, and mitotic processes, but down-regulate global immune regulation pathways. Taken together, these results suggest profound alterations in gene regulation in ecDNA-containing tumors, shedding light on molecular processes that give rise to their development and progression., Competing Interests: ML, SJ No competing interests declared, JL J.L. receives compensation as a consultant for Boundless Bio, HC Reviewing editor, eLife, SW S. Wu is a member of the scientific advisory board of Dimension Genomics Inc, PM P.S.M. is a co-founder and advisor of Boundless Bio. J.L. receives compensation as a consultant for Boundless Bio, VB V.B. is a co-founder, paid consultant, SAB member and has equity interest in Boundless Bio, Inc and Abterra Biosciences, Inc, (© 2023, Lin et al.)

Background: Most tail-anchored (TA) membrane proteins are delivered to the endoplasmic reticulum through a conserved posttranslational pathway. Although core mechanisms underlying the targeting and insertion of TA proteins are well established in eukaryotes, their role in mediating TA protein biogenesis in plants remains unclear. We reported the crystal structures of algal arsenite transporter 1 (ArsA1), which possesses an approximately 80-kDa monomeric architecture and carries chloroplast-localized TA proteins. However, the mechanistic basis of ArsA2, a Get3 (guided entry of TA proteins 3) homolog in plants, for TA recognition remains unknown., Results: Here, for the first time, we present the crystal structures of the diatom Pt-Get3a that forms a distinct ellipsoid-shaped tetramer in the open (nucleotide-bound) state through crystal packing. Pulldown assay results revealed that only tetrameric Pt-Get3a can bind to TA proteins. The lack of the conserved zinc-coordination CXXC motif in Pt-Get3a potentially leads to the spontaneous formation of a distinct parallelogram-shaped dimeric conformation in solution, suggesting a new dimer state for subsequent tetramerization upon TA targeting. Pt-Get3a nonspecifically binds to different subsets of TA substrates due to the lower hydrophobicity of its α-helical subdomain, which is implicated in TA recognition., Conclusions: Our study provides new insights into the mechanisms underlying TA protein shielding by tetrameric Get3 during targeting to the diatom's cell membrane., (© 2024. The Author(s).)

Peripheral CD8 + T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8 + T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors. Tolerant cells diverged early and progressively from effector cells, adopting a transcriptionally and epigenetically distinct state within 60 h of antigen encounter. Breaching tolerance required the synergistic actions of strong T cell receptor (TCR) signaling and inflammation, which cooperatively induced gene modules that enhanced protein translation. Weak TCR signaling during bystander infection failed to breach tolerance due to the uncoupling of effector gene expression from protein translation. Thus, tolerance engages a distinct differentiation trajectory enforced by protein translation defects., Competing Interests: Declaration of interests I.A.P. receives research funding from AstraZeneca and Bristol-Myers Squibb. H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, and Orbital Therapeutics, and is an advisor for 10× Genomics, Arsenal Biosciences, Chroma Medicine, and Spring Discovery., (Copyright © 2024 Elsevier Inc. All rights reserved.)

RNA splicing is pivotal in post-transcriptional gene regulation, yet the exponential expansion of intron length in humans poses a challenge for accurate splicing. Here, we identify hnRNPM as an essential RNA-binding protein that suppresses cryptic splicing through binding to deep introns, maintaining human transcriptome integrity. Long interspersed nuclear elements (LINEs) in introns harbor numerous pseudo splice sites. hnRNPM preferentially binds at intronic LINEs to repress pseudo splice site usage for cryptic splicing. Remarkably, cryptic exons can generate long dsRNAs through base-pairing of inverted ALU transposable elements interspersed among LINEs and consequently trigger an interferon response, a well-known antiviral defense mechanism. Significantly, hnRNPM-deficient tumors show upregulated interferon-associated pathways and elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity by repressing cryptic splicing and suggest that targeting hnRNPM in tumors may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance., Competing Interests: Declaration of interests R.A.F. is a co-founder, board of directors member, and stockholder of GanNA Bio and a board of directors member and stockholder of Chronus Health. H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, and Orbital Therapeutics, an advisor of 10× Genomics, Arsenal Biosciences, Chroma Medicine, and Spring Discovery, and a member of the Molecular Cell advisory board. E.L.V.N. is a co-founder, member of the board of directors, on the SAB, an equity holder, and a paid consultant for Eclipse BioInnovations, on the SAB of RNAConnect, and an inventor of intellectual property owned by University of California, San Diego. E.L.V.N.’s interests have been reviewed and approved by the Baylor College of Medicine in accordance with its conflict-of-interest policies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Circular RNAs (circRNAs) are stable RNAs present in cell-free RNA, which may comprise cellular debris and pathogen genomes. Here, we investigate the phenomenon and mechanism of cellular uptake and intracellular fate of exogenous circRNAs. Human myeloid cells and B cells selectively internalize extracellular circRNAs. Macrophage uptake of circRNA is rapid, energy dependent, and saturable. CircRNA uptake can lead to translation of encoded sequences and antigen presentation. The route of internalization influences immune activation after circRNA uptake, with distinct gene expression programs depending on the route of RNA delivery. Genome-scale CRISPR screens and chemical inhibitor studies nominate macrophage scavenger receptor MSR1, Toll-like receptors, and mTOR signaling as key regulators of receptor-mediated phagocytosis of circRNAs, a dominant pathway to internalize circRNAs in parallel to macropinocytosis. These results suggest that cell-free circRNA serves as an "eat me" signal and danger-associated molecular pattern, indicating orderly pathways of recognition and disposal., Competing Interests: Declaration of interests H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, and Orbital Therapeutics and is an advisor of 10x Genomics, Arsenal Biosciences, Chroma Medicine, Exai Bio, and Spring Discovery. H.Y.C. is a member of the Molecular Cell advisory board. R.M. is on the advisory boards of Kodikaz Therapeutic Solutions, Orbital Therapeutics, and 858 Therapeutics and is an inventor on a number of patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. B.A. is a current employee at Eli Lilly., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether hypotensive patients diagnosed with heart failure and reduced ejection fraction (HFrEF) might benefit from angiotensin receptor-neprilysin inhibitors (ARNis) in real-world practice because patients with baseline systolic blood pressure (SBP) of less than 100 mm Hg have been excluded from landmark trials., Patients and Methods: In this multicenter study conducted between January 1, 2013, and December 31, 2021, a total of 7562 symptomatic patients with HFrEF were enrolled and grouped by SBP (hypotension was defined as an SBP of less than 100 mm Hg) and ARNi use as follows: group 1, hypotensive/non-ARNi users (n=484); group 2, hypotensive/ARNi users (n=308); group 3, nonhypotensive/non-ARNi users (n=4560); and group 4, nonhypotensive/ARNi users (n=2210). Inverse probability of treatment weighting was used to balance baseline characteristics for survival analysis., Results: Diverse baseline characteristics and lower rates of medication use were found among non-ARNi users compared with ARNi users. Hypotensive/ARNi users had lower ARNi initiation doses than nonhypotensive/ARNi users. We observed significantly lower mortality, composite heart failure hospitalization, and CV death for hypotensive/ARNi and the other 2 nonhypotensive groups (groups 3 and 4) during a median follow-up of 3.43 years (all P<.05), with a similar effect on reverse remodeling for the hypotensive/ARNi group compared with the hypotensive/non-ARNi group. The event-free survival benefits of ARNi vs renin-angiotensin system inhibitors were consistent with the lower boundary of SBP for clinical benefits found until 88 mm Hg (spline curves) after inverse probability of treatment weighting., Conclusion: Patients with HFrEF and hypotension may still benefit from ARNi treatment. Patients with hypotensive HFrEF should not be routinely excluded from ARNi use in a real-world setting., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Crispr/CAS9-enabled homologous recombination to insert a tag in frame with an endogenous gene can circumvent difficulties such as context-dependent promoter activity that complicate analysis of gene expression and protein accumulation patterns. However, there have been few reports examining whether such gene targeting/gene tagging (GT) can alter expression of the target gene. The enzyme encoded by Δ 1 -pyrroline-5-carboxylate synthetase 1 (P5CS1) is key for stress-induced proline synthesis and drought resistance, yet its expression pattern and protein localisation have been difficult to assay. We used GT to insert YFP in frame with the 5' or 3' ends of the endogenous P5CS1 and At14a-Like 1 (AFL1) coding regions. Insertion at the 3' end of either gene generated homozygous lines with expression of the gene-YFP fusion indistinguishable from the wild type allele. However, for P5CS1 this occurred only after selfing and advancement to the T 5 generation allowed initial homozygous lethality of the insertion to be overcome. Once this was done, the GT-generated P5CS1-YFP plants revealed new information about P5CS1 localisation and tissue-specific expression. In contrast, insertion of YFP at the 5' end of either gene blocked expression. The results demonstrate that GT can be useful for functional analyses of genes that are problematic to properly express by other means but also show that, in some cases, GT can disrupt expression of the target gene., (© 2024 John Wiley & Sons Ltd.)

Background: Vascular access dysfunction is a great burden for hemodialysis patients. Early intervention of a dysfunctional arteriovenous shunt is associated with higher technical success and may improve midterm patency. This trial aimed to estimate the feasibility of a new system, the "rapid intervention team" (RIT) strategy., Methods: We recruited hemodialysis patients who visited our hospital because of arteriovenous shunt dysfunction or failure to undergo an RIT strategy from September 1, 2019 to December 31, 2022. In addition, we included a control group comprising patients who underwent percutaneous intervention for arteriovenous shunt dysfunction or failure before this strategy was implemented from February 1, 2017 to December 31, 2022. Case number, time to intervention, all-cause mortality, cumulative survival rate, and number of patients who required temporary dialysis catheter insertion and recreation were compared between the two groups. The primary endpoints were double-lumen insertion, a composite outcome involving permanent catheter insertion, and the need for recreation. The secondary endpoint was all-cause mortality., Results: We enrolled 1054 patients, including 544 (51.6%) and 510 (48.4%) in the RIT and control groups, respectively. Even with the coronavirus disease of 2019 (COVID-19) pandemic, the number of cases significantly increased after the implementation of the RIT strategy (from 216 in 2019 to 828 in 2022, p for trend <0.001). The RIT group had a shortened time to intervention ( p for trend <0.001). The implementation of the RIT strategy was significantly associated with a reduced risk of insertion of a temporary double-lumen catheter and recreation of vascular access (1% vs 6% and 1% vs 28%, respectively; both p < 0.01). The cumulative survival rate was not significantly different between the RIT and control groups ( p = 0.16)., Conclusion: The implementation of the RIT strategy improves the quantity and quality of percutaneous transluminal intervention for arteriovenous shunt dysfunction or failure in patients undergoing hemodialysis., Competing Interests: Conflicts of interest: The authors declare that there are no conflicts of interest related to the subject matter or materials discussed in the article., (Copyright © 2024, the Chinese Medical Association.)

Cinnamomum osmophloeum Kanehira (CO) is an endemic species of Taiwan. This study elucidated the composition of CO hydrosol, revealing trans -cinnamaldehyde (65.03%), trans -cinnamyl acetate (7.57%), and coumarin (4.31%) as the main volatile compounds. Seven compounds were identified in the water fraction of hydrosol, including a novel compound, 2-(2-hydroxyphenyl)oxetan-3-ol. This marks the first investigation into high-polarity compounds in hydrosol, extending beyond the volatile components. Notably, two compounds, trans -phenyloxetan-3-ol and cis -phenyloxetan-3-ol, demonstrated significant inhibition activity against phosphodiesterase type five (PDE5), with IC50 values of 4.37 µM and 3.40 µM, respectively, indicating their potential as novel PDE5 inhibitors. Furthermore, CO hydrosol was evaluated against enzymes associated with erectile dysfunction, namely acetylcholinesterase (AChE), angiotensin-I converting enzyme (ACE), and arginase type 2 (ARG2). These findings underscore the potential of CO hydrosol to modulate erectile function through diverse physiological pathways, hinting at its prospects for future development in a beverage or additive with enhanced effects on erectile function.

Selective RNA delivery is required for the broad implementation of RNA clinical applications, including prophylactic and therapeutic vaccinations, immunotherapies for cancer, and genome editing. Current polyanion delivery relies heavily on cationic amines, while cationic guanidinium systems have received limited attention due in part to their strong polyanion association, which impedes intracellular polyanion release. Here, we disclose a general solution to this problem in which cationic guanidinium groups are used to form stable RNA complexes upon formulation but at physiological pH undergo a novel charge-neutralization process, resulting in RNA release. This new delivery system consists of guanidinylated serinol moieties incorporated into a charge-altering releasable transporter (GSer-CARTs). Significantly, systematic variations in structure and formulation resulted in GSer-CARTs that exhibit highly selective mRNA delivery to the lung (∼97%) and spleen (∼98%) without targeting ligands. Illustrative of their breadth and translational potential, GSer-CARTs deliver circRNA, providing the basis for a cancer vaccination strategy, which in a murine model resulted in antigen-specific immune responses and effective suppression of established tumors.

CRISPR perturbation methods are limited in their ability to study non-coding elements and genetic interactions. In this study, we developed a system for bidirectional epigenetic editing, called CRISPRai, in which we apply activating (CRISPRa) and repressive (CRISPRi) perturbations to two loci simultaneously in the same cell. We developed CRISPRai Perturb-seq by coupling dual perturbation gRNA detection with single-cell RNA sequencing, enabling study of pooled perturbations in a mixed single-cell population. We applied this platform to study the genetic interaction between two hematopoietic lineage transcription factors, SPI1 and GATA1, and discovered novel characteristics of their co-regulation on downstream target genes, including differences in SPI1 and GATA1 occupancy at genes that are regulated through different modes. We also studied the regulatory landscape of IL2 (interleukin-2) in Jurkat T cells, primary T cells and chimeric antigen receptor (CAR) T cells and elucidated mechanisms of enhancer-mediated IL2 gene regulation. CRISPRai facilitates investigation of context-specific genetic interactions, provides new insights into gene regulation and will enable exploration of non-coding disease-associated variants., (© 2024. The Author(s).)

Background: Cancer-intrinsic type I interferon (IFN-I) production triggered by radiotherapy (RT) is mainly dependent on cytosolic double-stranded DNA (dsDNA)-mediated cGAS/STING signaling and increases cancer immunogenicity and enhances the antitumor immune response to increase therapeutic efficacy. However, cGAS/STING deficiency in colorectal cancer (CRC) may suppress the RT-induced antitumor immunity. Therefore, we aimed to evaluate the importance of the dsRNA-mediated antitumor immune response induced by RT in patients with CRC., Methods: Cytosolic dsRNA level and its sensors were evaluated via cell-based assays (co-culture assay, confocal microscopy, pharmacological inhibition and immunofluorescent staining) and in vivo experiments. Biopsies and surgical tissues from patients with CRC who received preoperative chemoradiotherapy (neoCRT) were collected for multiplex cytokine assays, immunohistochemical analysis and SNP genotyping. We also generated a cancer-specific adenovirus-associated virus (AAV)-IFNβ1 construct to evaluate its therapeutic efficacy in combination with RT, and the immune profiles were analyzed by flow cytometry and RNA-seq., Results: Our studies revealed that RT stimulates the autonomous release of dsRNA from cancer cells to activate TLR3-mediated IFN-I signatures to facilitate antitumor immune responses. Patients harboring a dysfunctional TLR3 variant had reduced serum levels of IFN-I-related cytokines and intratumoral CD8 + immune cells and shorter disease-free survival following neoCRT treatment. The engineered cancer-targeted construct AAV-IFNβ1 significantly improved the response to RT, leading to systematic eradication of distant tumors and prolonged survival in defective TLR3 preclinical models., Conclusion: Our results support that increasing cancer-intrinsic IFNβ1 expression is an immunotherapeutic strategy that enhances the RT-induced antitumor immune response in locally patients with advanced CRC with dysfunctional TLR3., Competing Interests: Competing interests: None declared., (© 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.)

The impact of leptin resistance on intestinal mucosal barrier integrity, appetite regulation, and hepatic lipid metabolism through the microbiota-gut-brain-liver axis has yet to be determined. Water extract of Phyllanthus emblica L. fruit (WEPE) and its bioactive compound gallic acid (GA) effectively alleviated methylglyoxal (MG)-triggered leptin resistance in vitro . Therefore, this study investigated how WEPE and GA intervention relieve leptin resistance-associated dysfunction in the intestinal mucosa, appetite, and lipid accumulation through the microbiota-gut-brain-liver axis in high-fat diet (HFD)-fed rats. The results showed that WEPE and GA significantly reduced tissues (jejunum, brain, and liver) MG-evoked leptin resistance, malondialdehyde (MDA), proinflammatory cytokines, SOCS3, orexigenic neuropeptides, and lipid accumulation through increasing leptin receptor, tight junction proteins, antimicrobial peptides, anorexigenic neuropeptides, excretion of fecal triglyceride (TG), and short-chain fatty acids (SCFAs) via a positive correlation with the Allobaculum and Bifidobacterium microbiota. These novel findings suggest that WEPE holds the potential as a functional food ingredient for alleviating obesity and its complications.

The human genome is pervasively transcribed and produces a wide variety of long non-coding RNAs (lncRNAs), constituting the majority of transcripts across human cell types. Some specific nuclear lncRNAs have been shown to be important regulatory components acting locally. As RNA-chromatin interaction and Hi-C chromatin conformation data showed that chromatin interactions of nuclear lncRNAs are determined by the local chromatin 3D conformation, we used Hi-C data to identify potential target genes of lncRNAs. RNA-protein interaction data suggested that nuclear lncRNAs act as scaffolds to recruit regulatory proteins to target promoters and enhancers. Nuclear lncRNAs may therefore play a role in directing regulatory factors to locations spatially close to the lncRNA gene. We provide the analysis results through an interactive visualization web portal at https://fantom.gsc.riken.jp/zenbu/reports/#F6&#95;3D&#95;lncRNA., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Agrawal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic prostatitis is a process of kidney deficiency and blood stasis mixed with various pathological factors involving the essence chamber, which is manifested as kidney deficiency and blood stasis. Based on the concept of the "brain-heart-kidney-essence chamber" axis of medication, Xiongji Formula is applied to the treatment of chronic prostatitis, due to its "simultaneous holistic and local action" and effects of tonifying the kidney yang and assisting the systemic yang, acting on the brain, heart and kidney as a whole, and meanwhile activating blood circulation, eliminating blood stasis and restoring the function of the essence chamber. This paper discusses the etiology and pathogenesis of chronic prostatitis with kidney deficiency and blood stasis in Chinese medicine, expounds the significance of "brain-heart-kidney-essence chamber" axis of medication, and explores the specific value and clinical application of Xiongji Formula.

Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior. Despite multimodality therapy, local and distant relapse rates remain high. Therefore, neoadjuvant chemotherapy (NACT) is employed to improve the R0 resection rates and survival, but its benefits remain controversial. Herein, we investigate pathologic and molecular correlates to NACT-induced histologic response in a group of 29 breast AS, 4 primary and 25 radiation-associated (RA). The two NACT regimens applied were anthracycline- and non-anthracycline-based. The pathologic response grade was defined as: I: ≤ 50%, II: 51%-90%, III: 91%-99%, and IV: 100%. An additional 45 primary AS and 102 RA-AS treated by surgery alone were included for survival comparison. The genomic landscape was analyzed in a subset of cases and compared to a cohort of AS without NACT on a paired tumor-normal targeted DNA NGS platform. All patients were females, with a median age of 31 years in primary AS and 68 years in RA-AS. All surgical margins were negative in NACT group. The NACT response was evenly divided between poor (Grades I-II; n = 15) and good responders (Grades III-IV; n = 14). Mitotic count >10/mm 2 was the only factor inversely associated with pathologic response. By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations. TMB or other genomic alterations did not correlate with pathologic response. All four patients with Grade IV response remained free of disease. The good responders had a significantly better disease-specific survival (p = 0.04). There was no survival difference with NACT status or the NACT regimens applied. However, NACT patients with MYC-amplified tumors showed better disease-free survival (p = 0.04) compared to MYC-amplified patients without NACT. The overall survival of NACT group correlated with size >10 cm (p = 0.02), pathologic response (p = 0.04), and multifocality (p = 0.01) by univariate, while only size >10 cm (p = 0.03) remained significant by multivariate analysis., (© 2024 Wiley Periodicals LLC.)

Background: Prognostic indices can enhance personalized predictions of health burdens. However, a simple, practical, and reproducible tool is lacking for clinical use. This study aimed to develop a machine learning-based prognostic index for predicting all-cause mortality in community-dwelling older individuals., Methods: We utilized the Healthy Aging Longitudinal Study in Taiwan (HALST) cohort, encompassing data from 5 663 participants. Over the 5-year follow-up, 447 deaths were confirmed. A machine learning-based routine blood examination prognostic index (MARBE-PI) was developed using common laboratory tests based on machine learning techniques. Participants were grouped into multiple risk categories by stratum-specific likelihood ratio analysis based on their MARBE-PI scores. The MARBE-PI was subsequently externally validated with an independent population-based cohort from Japan., Results: Beyond age, sex, education level, and BMI, 6 laboratory tests (low-density lipoprotein, albumin, aspartate aminotransferase, lymphocyte count, high-sensitivity C-reactive protein, and creatinine) emerged as pivotal predictors via stepwise logistic regression (LR) for 5-year mortality. The area under curves of MARBE-PI constructed by LR were 0.799 (95% confidence interval [95% CI]: 0.778-0.819) and 0.756 (95% CI: 0.694-0.814) for the internal and external validation data sets, and were 0.801 (95% CI: 0.790-0.811) and 0.809 (95% CI: 0.774-0.845) for the extended 10-year mortality in both data sets, respectively. Risk categories stratified by MARBE-PI showed a consistent dose-response association with mortality. The MARBE-PI also performed comparably with indices constructed with clinical health deficits and/or laboratory results., Conclusions: The MARBE-PI is considered the most applicable measure for risk stratification in busy clinical settings. It holds potential to pinpoint older individuals at elevated mortality risk, thereby aiding clinical decision-making., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Honokiol is a natural polyphenolic compound extracted from Magnolia officinali, which is commonly used material in Chinese herbal medicine, has a variety of biological functions, including anti-tumor, anti-oxidant, anti-inflammation, anti-microbial and anti-allergy. Although honokiol has numerous beneficial effects on human diseases, the underlying mechanisms of tumor metastasis are still unclear. Previously, we reported that honokiol suppresses thyroid cancer cell proliferation with cytotoxicity through cell cycle arrest, apoptosis, and dysregulation of intracellular hemostasis. Herein, we hypothesized that the antioxidant effect of honokiol might play a critical role in thyroid cancer cell proliferation and migration., Methods: The cell viability assays, cellular reactive oxygen species (ROS) activity, cell migration, and immunoblotting were performed after cells were treated with honokiol., Results: Based on this hypothesis, we first demonstrated that honokiol suppresses cell proliferation in two human anaplastic thyroid carcinoma (ATC) cell lines, KMH-2 and ASH-3, within a dosage- and time-dependent manner by cell counting kit-8 (CCK-8) assay. Next, we examined that honokiol induced ROS activation and could be suppressed by pre-treated with an antioxidant agent, N-acetyl-l-cysteine (NAC). Furthermore, the honokiol suppressed cell proliferation can be rescued by pre-treated with NAC. Finally, we demonstrated that honokiol inhibited ATC cell migration by modulating epithelial-mesenchymal transition (EMT)-related markers by Western blotting., Conclusion: Taken together, we provided the potential mechanism for treating ATC cells with honokiol, which significantly suppresses tumor proliferation and inhibits tumor metastasis in vitro through reactive oxygen species (ROS) induction., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: This study investigated whether initial SGLT2 (sodium-glucose cotransporter 2) inhibitor-based treatment is superior to metformin-based regimens as a primary prevention strategy among low-risk patients with diabetes., Methods and Results: In this nationwide cohort study, a total of 38 496 patients with diabetes with low cardiovascular risk were identified (age 62.0±11.6 years, men 50%) from January 1 to December 31, 2016. Patients receiving SGLT2 inhibitors-based and metformin-based regimens were 1:2 matched by propensity score. Study outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, stroke, and progression to end-stage renal disease. Compared with 1928 patients receiving metformin-based regimens, 964 patients receiving SGLT2 inhibitor-based regimens had similar all-cause mortality (hazard ratio [HR], 0.75 [95% CI, 0.51-1.12]), cardiovascular death (HR, 0.69 [95% CI, 0.25-1.89]), hospitalization for heart failure (HR, 1.06 [95% CI, 0.59-1.92]), stroke (HR, 0.78 [95% CI, 0.48-1.27]), and progression to end-stage renal disease (HR, 0.88 [95% CI, 0.32-2.39]). However, SGLT2 inhibitors were associated with a lower risk of all-cause mortality (HR, 0.47 [95% CI, 0.23-0.99]; P for interaction=0.008) and progression to end-stage renal disease (HR, 0.22 [95% CI, 0.06-0.82]; P for interaction=0.04) in patients under the age of 65., Conclusions: In comparison to metformin-based regimens, SGLT2 inhibitor-based regimens showed a similar risk of all-cause mortality and adverse cardiorenal events. SGLT2 inhibitors might be considered as first-line therapy in select low-risk patients, for example, younger patients with diabetes.

Current immune checkpoint inhibiters (ICIs) have contrasting clinical results in poorly immunogenic cancers such as microsatellite-stable colorectal cancer (MSS-CRC). Therefore, understanding and developing the combinational therapeutics for ICI-unresponsive cancers is critical. Here, we demonstrated that the novel topoisomerase I inhibitor TLC388 can reshape the tumor immune landscape, corroborating their antitumor effects combined with radiotherapy as well as immunotherapy. We found that TLC388 significantly triggered cytosolic single-stranded DNA (ssDNA) accumulation for STING activation, leading to type I interferons (IFN-Is) production for increased cancer immunogenicity to enhance antitumor immunity. TLC388-treated tumors were infiltrated by a vast number of dendritic cells, immune cells, and costimulatory molecules, contributing to the favorable antitumor immune response within the tumor microenvironment. The infiltration of cytotoxic T and NK cells were more profoundly existed within tumors in combination with radiotherapy and ICIs, leading to superior therapeutic efficacy in poorly immunogenic MSS-CRC. Taken together, these results showed that the novel topoisomerase I inhibitor TLC388 increased cancer immunogenicity by ssDNA/STING-mediated IFN-I production, enhancing antitumor immunity for better therapeutic efficacy in combination with radiotherapy and ICIs for poorly immunogenic cancer., (© 2024. The Author(s).)

Long noncoding RNAs (lncRNAs) are a class of RNA molecules exceeding 200 nucleotides in length that lack long open-reading frames. Transcribed predominantly by RNA polymerase II (>500nt), lncRNAs can undergo splicing and are produced from various regions of the genome, including intergenic regions, introns, and in antisense orientation to protein-coding genes. Aberrations in lncRNA expression or function have been associated with a wide variety of diseases, including cancer, cardiovascular diseases, diabetes, and neurodegeneration. Despite the growing recognition of select lncRNAs as key players in cellular processes and diseases, several challenges obscure a comprehensive understanding of their functional landscape. Recent technological innovations, such as in sequencing, affinity-based techniques, imaging, and RNA perturbation, have advanced functional characterization and mechanistic understanding of disease-associated lncRNAs., Competing Interests: Declaration of Competing Interest H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, and Orbital Therapeutics, and is an advisor to 10x Genomics, Arsenal Biosciences, Chroma Medicine, and Spring Discovery., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aimed to investigate the distinct yet interconnected aspects of social isolation, namely living alone and loneliness, and their individual and combined effects on predicting health-related quality of life (HRQoL)., Methods: A comprehensive analysis, encompassing both cross-sectional and longitudinal approaches, was conducted using a nationally representative sample of 5644 community-dwelling adults aged 55 and older from the Healthy Aging Longitudinal Study in Taiwan (HALST)., Results: Baseline data revealed that 9% of the sample reported living alone, while 10.3% reported experiencing loneliness, with 2.5% reporting both living alone and feeling lonely. Regression analyses consistently demonstrated that loneliness was significantly associated with concurrent and subsequent lower physical (PCS) and mental (MCS) component of HRQoL. Conversely, additional analyses indicated that living alone could indirectly exacerbate the adverse effects of loneliness or contribute to prolonged feelings of loneliness, subsequently predicting lower HRQoL after 3.2 year., Conclusion: In terms of practical implications, interventions and policies aiming to enhance HRQoL in older adults should give particular attention to those who report feelings of loneliness, especially individuals living alone., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Endovascular intervention for thrombosed aneurysmal arteriovenous fistula (AVF) is still a challenge. Manual compression technique (MCT)-assisted angioplasty may be helpful, but there is no evidence or data to support it., Methods: From January 2018 to May 2021, patients with thrombosed aneurysmal AVFs were retrospectively enrolled. The patients were separated into the MCT group or the traditional group according to the procedure received. Technical failure, clinical failure, 90-day patency, and safety were analyzed., Results: A total of 159 cases (64 ± 12 years old, 60% male) were enrolled, of which 87 cases received MCT and 72 underwent traditional angioplasty. No technical failure was observed in the MCT group, while five technical failures were observed in the traditional group (0% vs. 7%, p = 0.02). There were no differences in the clinical failure rate (3% vs. 7%, p = 0.30), 90-day patency rate, or procedure time between the MCT group and the traditional group. There was no symptomatic pulmonary embolism or other complication in the two groups., Conclusion: MCT is a low-cost, less invasive, and safe procedure for thrombosed aneurysmal AVF, and it achieves a higher technical success rate than traditional angioplasty., (© 2022 Wiley Periodicals LLC.)

Breast cancer (BC) represents one of the most prevalent malignant threats to women globally. Tumor relapse or metastasis is facilitated by BC stemness progression, contributing to tumorigenicity. Therefore, comprehending the characteristics of stemness progression and the underlying molecular mechanisms is pivotal for BC advancement. Hinokitiol (β-thujaplicin), a tropolone-related compound abundant in the heartwood of cupressaceous plants, exhibits antimicrobial activity. In our study, we employed three BC cell lines (MDA-MB-231, MCF-7, and T47D) to assess the expression of stemness-, apoptosis-, and autophagy-related proteins. Hinokitiol significantly reduced the viability of cancer cells in a dose-dependent manner. Furthermore, we observed that hinokitiol enhances apoptosis by increasing the levels of cleaved poly-ADP-ribose polymerase (PARP) and phospho-p53. It also induces dysfunction in autophagy through the upregulation of LC3B and p62 protein expression. Additionally, hinokitiol significantly suppressed the number and diameter of cancer cell line spheres by reducing the expression of cluster of differentiation44 (CD44) and key transcription factors. These findings underscore hinokitiol's potential as a therapeutic agent for breast cancer, particularly as a stemness-progression inhibitor. Further research and clinical studies are warranted to explore the full therapeutic potential of hinokitiol in the treatment of breast cancer.

We aimed to analyze the different patient characteristics and treatment outcomes (such as sustained viral response, SVR) between incarcerated patients with chronic hepatitis C (CHC) and those with CHC from the outpatient department through an on-site integrated screening and microelimination program in a detection center. In this retrospective study, which ran from May 2021 to April 2022, we included 32 consenting male prisoners aged at least 20 years who were willing to participate in the study. Members of the control group (who received DAAs in an outpatient setting) were selected from the treated CHC patient databank of individuals who received DAA regimens at Chi Mei Hospital between January 2021 and December 2022. The patients in the two groups did not differ significantly in terms of age, FIB-4 score, HCV RNA, HBV coinfection, hemogram findings, coagulation profiles, and renal function tests. However, the patients in the incarcerated group had a significantly different genotype distribution compared to the control group, significantly lower liver enzyme levels, and higher albumin and bilirubin levels compared to those in the control group. The rate of SVR to DAA treatment obtained among incarcerated patients did not differ significantly from that obtained among patients in the control group. Loss to follow-up (for several reasons) is a major reason for treatment discontinuation among these patients., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024 Hsuan-Yuan Chang et al.)

In this study, a sulfonation approach using chlorosulfonic acid (CSA) to prepare cellulose sulfate nanofibers (CSNFs) from raw jute fibers is demonstrated. Both elemental sulfur content and zeta potential in the CSNFs are found to increase with increasing CSA content used. However, the corresponding crystallinity in the CSNFs decreases with the increasing amount of CSA used due to degradation of cellulose chains under harsh acidic conditions. The ammonium adsorption results from the CSNFs with varying degrees of sulfonation were analyzed using the Langmuir isotherm model, and the analysis showed a very high maximum ammonium adsorption capacity (41.1 mg/g) under neutral pH, comparable to the best value from a synthetic hydrogel in the literature. The high ammonium adsorption capacity of the CSNFs was found to be maintained in a broad acidic range (pH = 2.5 to 6.5).

Background: Patients with unmet social needs and social determinants of health (SDOH) challenges continue to face a disproportionate risk of increased prevalence of disease, health care use, higher health care costs, and worse outcomes. Some existing predictive models have used the available data on social needs and SDOH challenges to predict health-related social needs or the need for various social service referrals. Despite these one-off efforts, the work to date suggests that many technical and organizational challenges must be surmounted before SDOH-integrated solutions can be implemented on an ongoing, wide-scale basis within most US-based health care organizations., Objective: We aimed to retrieve available information in the electronic health record (EHR) relevant to the identification of persons with social needs and to develop a social risk score for use within clinical practice to better identify patients at risk of having future social needs., Methods: We conducted a retrospective study using EHR data (2016-2021) and data from the US Census American Community Survey. We developed a prospective model using current year-1 risk factors to predict future year-2 outcomes within four 2-year cohorts. Predictors of interest included demographics, previous health care use, comorbidity, previously identified social needs, and neighborhood characteristics as reflected by the area deprivation index. The outcome variable was a binary indicator reflecting the likelihood of the presence of a patient with social needs. We applied a generalized estimating equation approach, adjusting for patient-level risk factors, the possible effect of geographically clustered data, and the effect of multiple visits for each patient., Results: The study population of 1,852,228 patients included middle-aged (mean age range 53.76-55.95 years), White (range 324,279/510,770, 63.49% to 290,688/488,666, 64.79%), and female (range 314,741/510,770, 61.62% to 278,488/448,666, 62.07%) patients from neighborhoods with high socioeconomic status (mean area deprivation index percentile range 28.76-30.31). Between 8.28% (37,137/448,666) and 11.55% (52,037/450,426) of patients across the study cohorts had at least 1 social need documented in their EHR, with safety issues and economic challenges (ie, financial resource strain, employment, and food insecurity) being the most common documented social needs (87,152/1,852,228, 4.71% and 58,242/1,852,228, 3.14% of overall patients, respectively). The model had an area under the curve of 0.702 (95% CI 0.699-0.705) in predicting prospective social needs in the overall study population. Previous social needs (odds ratio 3.285, 95% CI 3.237-3.335) and emergency department visits (odds ratio 1.659, 95% CI 1.634-1.684) were the strongest predictors of future social needs., Conclusions: Our model provides an opportunity to make use of available EHR data to help identify patients with high social needs. Our proposed social risk score could help identify the subset of patients who would most benefit from further social needs screening and data collection to avoid potentially more burdensome primary data collection on all patients in a target population of interest., (©Elham Hatef, Hsien-Yen Chang, Thomas M Richards, Christopher Kitchen, Janya Budaraju, Iman Foroughmand, Elyse C Lasser, Jonathan P Weiner. Originally published in JMIR Formative Research (https://formative.jmir.org), 12.03.2024.)

Background: Heart failure (HF) is a significant public health problem worldwide. Death and rehospitalization rates are similar across different HF phenotypes. However, the existing Taiwanese HF registries mainly enrolled inpatients with HF and reduced ejection fraction (HFrEF) before 2019, so their results may not apply to outpatients or patients with HF with mildly reduced ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF) phenotypes., Methods: The Taiwan Society of Cardiology Heart Failure Registry 2020 is a prospective, multicenter, observational registry that will enroll patients with HF from 27 hospitals in Taiwan between 2020 and 2022 and will be followed for two years. Patients eligible for enrollment include those admitted due to acute decompensated heart failure or outpatients with a history of hospitalization for heart failure within the past six months. The registry will collect patient demographics, medical history, HF diagnosis, medication use, examination results, and comorbidities. The registry plans to enroll 3,370 patients, with the distribution of HFrEF/HFmrEF/HFpEF as 59%/13%/28%. Follow-up intervals will occur every six months for up to two years to monitor clinical outcomes and major cardiac interventions. The registry will conclude in December 2024., Conclusions: The Taiwan Society of Cardiology Heart Failure Registry 2020 is a comprehensive and meticulous effort to demonstrate the epidemiology, adherence to guidelines, clinical outcomes, and disease progression of Taiwanese patients with HF in contemporary clinical practice., Competing Interests: All the authors declare no conflict of interest.