Purpose: Human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in various malignancies, including breast and gastric cancers, and is associated with poor prognosis. Although HER2-targeted therapies, such as trastuzumab, improve outcomes in HER2-positive tumors, resistance often develops, and HER2-low tumors remain largely untargeted. Trastuzumab deruxtecan (T-DXd; DS-8201a) is a HER2-targeted antibody-drug conjugate with potent activity in HER2-positive and HER2-low tumors. This study evaluates its antitumor mechanisms and efficacy in HER2-positive, HER2-low, and homologous recombination deficiency (HRD)–associated models. Materials and Methods: Effects of T-DXd were assessed in cancer cell lines with diverse HER2 expression and HRD status. In vivo efficacy was evaluated using a xenograft model derived from HER2-low SNU-601 gastric cancer cells. Results: T-DXd reduced HER2 phosphorylation and downstream signaling (AKT, ERK) in HER2-positive cells. It induced DNA damage accumulation, as evidenced by increased γH2AX and p-Chk1 expression, and triggered apoptosis through cleaved poly(ADP-ribose) polymerase and caspase-3 activation, confirmed by annexin V staining. Similar effects were observed in HER2-low cells, with greater sensitivity in HRD cells. In xenografts, T-DXd reduced tumor volume by up to 80% at 4 mg/kg and 10 mg/kg. Histological analyses showed decreased Ki-67 and increased apoptosis. Furthermore, T-DXd induced G2/M cell cycle arrest and nuclear anaplasia, suggesting disruption of chromosomal stability as a potential antitumor mechanism. No significant toxicity, including body weight loss, was observed. Conclusion These findings highlight T-DXd’s effectiveness in HER2-low and HRD tumors, supporting its broader clinical application, including strategies targeting DNA damage repair pathways.

Purpose: Sustained cell proliferation and cell cycle acceleration in cancer cells inherently increase DNA damage, which interferes with homeostatic replication and transcription. Ataxia telangiectasia and Rad3-related (ATR) is crucial for initiation of the DNA damage response, and ATR inhibitors, such as elimusertib, induce increased replication stress and DNA damage. We investigated the anti-tumor effects of elimusertib and its mechanism of action in relation to replication stress. Materials and Methods: Anti-tumor effects were evaluated by MTT assay and colony formation assay in breast cancer cell lines in vitro, in breast cancer cell xenografts in vivo, and in patient-derived xenograft models. Cell cycle was assessed by flow cytometry and BrdU assay was used to measure replicating cells and S-phase progression. Alkaline and neutral comet assay was used to measure single and double-stranded DNA damages, respectively. Results: Elimusertib delayed S-phase progression in MDA-MB-453 and MDA-MB-231 cells and induced caspase-7–dependent apoptosis. Furthermore, the increase in sub-G1 population in the fluorescence-activated cell sorting analysis and Annexin V assay also confirmed apoptotic cell death. In the BrdU assay, single-stranded DNA (ssDNA) increased in sensitive cells and aberrant ssDNA induced DNA damage in S-phase and eventually caused replication catastrophe. Finally, these anti-tumor effects were proven in in vivo xenograft and patient-derived xenograft models. Conclusion Elimusertib had anti-tumor effects and induced replication catastrophe in breast cancer cells with a high replication rate. Moreover, cells under high DNA replication stress were sensitive to elimusertib. Further studies and treatment strategies with elimusertib are warranted for cancers with a high replication rate.

Background/Aims: Cardiovascular disease is the leading cause of death worldwide. This study aimed to investigate the recent nationwide trends in major dietary risk factors for dyslipidemia and atherosclerosis. Methods: We estimated age-standardized mean intakes of fresh fruits, fresh vegetables, whole grains, dietary fiber, and sugar-sweetened beverages (SSBs); and mean percentage of energy intake from protein, total fat, saturated fat, and polyunsaturated fat using nationally representative samples from the Korean National Health Examination and Nutrition Survey 2013–2022. To assess overall diet quality, we calculated mean Korean Healthy Eating Index (KHEI) (range 0–100, higher scores indicating greater diet quality). Results: In 2013–2022, there were overall decreasing trends in age-standardized mean KHEI score and intakes of fresh fruits and vegetables, whole grains, and dietary fiber; and overall increasing trends in mean intakes of SSBs, protein, and dietary fat among both male and female. The KHEI score increased in older adults aged ≥ 60 years, whereas it decreased among younger adults. Throughout the study period, younger adults tended to have lower intakes of fresh fruits, fresh vegetables, and whole grains; higher intakes of SSBs, protein, and dietary fat; and lower KHEI score. The mean KHEI score was lower in male (vs. female) and lower (vs. higher) income groups. Conclusions Our data suggest that, from 2013 to 2022, there was a trend toward an unhealthy diet in Korean adults. Our findings also suggest dietary inequalities among age, sex, and income groups, suggesting the need for more intense interventions targeting the vulnerable populations.

Background/Aims: Cardiovascular disease is the leading cause of death worldwide. This study aimed to investigate the recent nationwide trends in major dietary risk factors for dyslipidemia and atherosclerosis. Methods: We estimated age-standardized mean intakes of fresh fruits, fresh vegetables, whole grains, dietary fiber, and sugar-sweetened beverages (SSBs); and mean percentage of energy intake from protein, total fat, saturated fat, and polyunsaturated fat using nationally representative samples from the Korean National Health Examination and Nutrition Survey 2013–2022. To assess overall diet quality, we calculated mean Korean Healthy Eating Index (KHEI) (range 0–100, higher scores indicating greater diet quality). Results: In 2013–2022, there were overall decreasing trends in age-standardized mean KHEI score and intakes of fresh fruits and vegetables, whole grains, and dietary fiber; and overall increasing trends in mean intakes of SSBs, protein, and dietary fat among both male and female. The KHEI score increased in older adults aged ≥ 60 years, whereas it decreased among younger adults. Throughout the study period, younger adults tended to have lower intakes of fresh fruits, fresh vegetables, and whole grains; higher intakes of SSBs, protein, and dietary fat; and lower KHEI score. The mean KHEI score was lower in male (vs. female) and lower (vs. higher) income groups. Conclusions Our data suggest that, from 2013 to 2022, there was a trend toward an unhealthy diet in Korean adults. Our findings also suggest dietary inequalities among age, sex, and income groups, suggesting the need for more intense interventions targeting the vulnerable populations.

Background/Aims: Cardiovascular disease is the leading cause of death worldwide. This study aimed to investigate the recent nationwide trends in major dietary risk factors for dyslipidemia and atherosclerosis. Methods: We estimated age-standardized mean intakes of fresh fruits, fresh vegetables, whole grains, dietary fiber, and sugar-sweetened beverages (SSBs); and mean percentage of energy intake from protein, total fat, saturated fat, and polyunsaturated fat using nationally representative samples from the Korean National Health Examination and Nutrition Survey 2013–2022. To assess overall diet quality, we calculated mean Korean Healthy Eating Index (KHEI) (range 0–100, higher scores indicating greater diet quality). Results: In 2013–2022, there were overall decreasing trends in age-standardized mean KHEI score and intakes of fresh fruits and vegetables, whole grains, and dietary fiber; and overall increasing trends in mean intakes of SSBs, protein, and dietary fat among both male and female. The KHEI score increased in older adults aged ≥ 60 years, whereas it decreased among younger adults. Throughout the study period, younger adults tended to have lower intakes of fresh fruits, fresh vegetables, and whole grains; higher intakes of SSBs, protein, and dietary fat; and lower KHEI score. The mean KHEI score was lower in male (vs. female) and lower (vs. higher) income groups. Conclusions Our data suggest that, from 2013 to 2022, there was a trend toward an unhealthy diet in Korean adults. Our findings also suggest dietary inequalities among age, sex, and income groups, suggesting the need for more intense interventions targeting the vulnerable populations.

Background/Aims: Cardiovascular disease is the leading cause of death worldwide. This study aimed to investigate the recent nationwide trends in major dietary risk factors for dyslipidemia and atherosclerosis. Methods: We estimated age-standardized mean intakes of fresh fruits, fresh vegetables, whole grains, dietary fiber, and sugar-sweetened beverages (SSBs); and mean percentage of energy intake from protein, total fat, saturated fat, and polyunsaturated fat using nationally representative samples from the Korean National Health Examination and Nutrition Survey 2013–2022. To assess overall diet quality, we calculated mean Korean Healthy Eating Index (KHEI) (range 0–100, higher scores indicating greater diet quality). Results: In 2013–2022, there were overall decreasing trends in age-standardized mean KHEI score and intakes of fresh fruits and vegetables, whole grains, and dietary fiber; and overall increasing trends in mean intakes of SSBs, protein, and dietary fat among both male and female. The KHEI score increased in older adults aged ≥ 60 years, whereas it decreased among younger adults. Throughout the study period, younger adults tended to have lower intakes of fresh fruits, fresh vegetables, and whole grains; higher intakes of SSBs, protein, and dietary fat; and lower KHEI score. The mean KHEI score was lower in male (vs. female) and lower (vs. higher) income groups. Conclusions Our data suggest that, from 2013 to 2022, there was a trend toward an unhealthy diet in Korean adults. Our findings also suggest dietary inequalities among age, sex, and income groups, suggesting the need for more intense interventions targeting the vulnerable populations.

Background/Aims: Cardiovascular disease is the leading cause of death worldwide. This study aimed to investigate the recent nationwide trends in major dietary risk factors for dyslipidemia and atherosclerosis. Methods: We estimated age-standardized mean intakes of fresh fruits, fresh vegetables, whole grains, dietary fiber, and sugar-sweetened beverages (SSBs); and mean percentage of energy intake from protein, total fat, saturated fat, and polyunsaturated fat using nationally representative samples from the Korean National Health Examination and Nutrition Survey 2013–2022. To assess overall diet quality, we calculated mean Korean Healthy Eating Index (KHEI) (range 0–100, higher scores indicating greater diet quality). Results: In 2013–2022, there were overall decreasing trends in age-standardized mean KHEI score and intakes of fresh fruits and vegetables, whole grains, and dietary fiber; and overall increasing trends in mean intakes of SSBs, protein, and dietary fat among both male and female. The KHEI score increased in older adults aged ≥ 60 years, whereas it decreased among younger adults. Throughout the study period, younger adults tended to have lower intakes of fresh fruits, fresh vegetables, and whole grains; higher intakes of SSBs, protein, and dietary fat; and lower KHEI score. The mean KHEI score was lower in male (vs. female) and lower (vs. higher) income groups. Conclusions Our data suggest that, from 2013 to 2022, there was a trend toward an unhealthy diet in Korean adults. Our findings also suggest dietary inequalities among age, sex, and income groups, suggesting the need for more intense interventions targeting the vulnerable populations.

Transcription factor CP2-like protein 1 (Tfcp2l1), a naïve pluripotency transcription factor, is expressed in both early embryonic and adult tissues, where it enforces pluripotency of embryonic stem cells (ESCs) and stemness features of cancer cells, respectively. However, the detailed molecular pathways by which Tfcp2l1 is regulated in early embryonic development and cancer cells remain unknown. Here, we identified the pseudophosphatase dual specificity phosphatase 27 (Dusp27), also known as serine/threonine/tyrosine-interacting like-2, as a novel Tfcp2l1-interacting protein through a sterile alpha motif-like domain in the C-terminus of Tfcp2l1 in murine ESCs. The interaction between Dusp27 and Tfcp2l1 was dependent on the cell cycle status and increased during mitosis. Expression of Dusp27 was upregulated during naïve pluripotency and repressed during spontaneous differentiation of murine ESCs. Ectopic expression of Dusp27 enhanced the transcriptional activity of Tfcp2l1 and promoted features associated with the naïve pluripotent state, while suppressing meso-endodermal lineage differentiation. The present study demonstrates that Dusp27 is a novel positive regulator of Tfcp2l1 through a physical interaction and thereby fine-tunes the pluripotency status and meso-endodermal differentiation of murine ESCs.

BACKGROUND: Currently, there is no apparent treatment for sarcopenia, which is characterized by diminished myoblast function. We aimed to manufacture exosomes that retain the myogenic differentiation capacity of human fetal cartilagederived progenitor cells (hFCPCs) and investigate their muscle regenerative efficacy in myoblasts and a sarcopenia rat model. METHODS: The muscle regeneration potential of exosomes (F-Exo) secreted during myogenic differentiation of hFCPCs was compared to human bone marrow mesenchymal stem cells-derived (hBMSCs) exosomes (B-Exo) in myoblasts and sarcopenia rat model. The effect of F-Exo was analyzed through known microRNAs (miRNAs) analysis. The mechanism of action of F-Exo was confirmed by measuring the expression of proteins involved in the Wnt signaling pathway. RESULTS: F-Exo and B-Exo showed similar exosome characteristics. However, F-Exo induced the expression of muscle markers (MyoD, MyoG, and MyHC) and myotube formation in myoblasts more effectively than B-Exo. Moreover, F-Exo induced greater increases in muscle fiber cross-sectional area and muscle mass compared to B-Exo in a sarcopenia rat. The miR-145-5p, relevant to muscle regeneration, was found in high concentrations in the F-Exo, and RNase pretreatment reduced the efficacy of exosomes. The effects of F-Exo on the expression of myogenic markers in myoblasts were paralleled by the miR-145-5p mimics, while the inhibitor partially negated this effect. F-Exo was involved in the Wnt signaling pathway by enhancing the expression of Wnt5a and b-catenin. CONCLUSION F-Exo improved muscle regeneration by activating the Wnt signaling pathway via abundant miR-145-5p, mimicking the remarkable myogenic differentiation potential of hFCPCs.

BACKGROUND: Current tendon and ligament reconstruction surgeries rely on scar tissue healing which differs from native bone-to-tendon interface (BTI) tissue. We aimed to engineer Synovium-derived mesenchymal stem cells (Sy-MSCs) based scaffold-free fibrocartilage constructs and investigate in vivo bone–tendon interface (BTI) healing efficacy in a rat anterior cruciate ligament (ACL) reconstruction model. METHODS: Sy-MSCs were isolated from knee joint of rats. Scaffold-free sy-MSC constructs were fabricated and cultured in differentiation media including TGF-b-only, CTGF-only, and TGF-b + CTGF. Collagenase treatment on tendon grafts was optimized to improve cell-to-graft integration. The effects of fibrocartilage differentiation and collagenase treatment on BTI integration was assessed by conducting histological staining, cell adhesion assay, and tensile testing. Finally, histological and biomechanical analyses were used to evaluate in vivo efficacy of fibrocartilage construct in a rat ACL reconstruction model. RESULTS: Fibrocartilage-like features were observed with in the scaffold-free sy-MSC constructs when applying TGF-band CTGF concurrently. Fifteen minutes collagenase treatment increased cellular attachment 1.9-fold compared to the Control group without affecting tensile strength. The failure stress was highest in the Col + D + group (22.494 ± 13.74 Kpa) compared to other groups at integration analysis in vitro. The ACL Recon + FC group exhibited a significant 88% increase in estimated stiffness (p = 0.0102) compared to the ACL Recon group at the 4-week postoperative period. CONCLUSION Scaffold-free, fibrocartilage engineering together with tendon collagenase treatment enhanced fibrocartilaginous BTI healing in ACL reconstruction.