Protective effect of genistein on radiation-induced intestinal injury in tumor bearing mice

BACKGROUND: Radiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes. METHODS: Mouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred. RESULTS: Genistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group. CONCLUSION: Genistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients

Anti-tumor effects of NK cells and anti-PD-L1 antibody with antibody-dependent cellular cytotoxicity in PD-L1-positive cancer cell lines

Background Although programmed cell death-1/programmed death-ligand 1 (PD-L1) inhibitors show remarkable antitumor activity, a large portion of patients with cancer, even those with high PD-L1-expressing tumors, do not respond to their effects. Most PD-L1 inhibitors contain modified fragment crystallizable region (Fc) receptor binding sites to prevent antibody-dependent cellular cytotoxicity (ADCC) against PD-L1-expressing non-tumor cells. However, natural killer (NK) cells have specific antitumor activity in the presence of tumor-targeting antibody through ADCC, which could enhance NK cell-induced cytotoxicity. We evaluated the antitumor efficacy of ADCC via anti-PD-L1 monoclonal antibodies (mAbs) and NK cells against several PD-L1-positive cancer cell lines. Methods Various cancer cell lines were used as target cell lines. Surface PD-L1 expression was analyzed by flow cytometry. IMC-001 and anti-hPD-L1-hIgG1 were tested as anti-PD-L1 mAbs with ADCC and atezolizumab as an anti-PD-L1 mAb without ADCC. NK cell cytotoxicity was measured by(51)Cr-release assay and CD107a degranulation assay. Also, live cell imaging was performed to evaluate cytotoxicity in a single-cell level. NK-92-CD16 (CD16-transduced NK-92 cell line) and peripheral blood mononuclear cells from healthy donors, respectively, were used as an effector cell. Fc gamma RIIIa (CD16a)-V158F genotyping was performed for healthy donors. Results We demonstrated that the cytotoxicity of NK-92-CD16 cells toward PD-L1-positive cancer cell lines was significantly enhanced in the presence of anti-PD-L1 mAb with ADCC. We also noted a significant increase in primary human NK cell cytotoxicity against PD-L1-positive human cancer cells when cocultured with anti-PD-L1 mAb with ADCC. Moreover, NK cells expressing aFCGR3Ahigh-affinity genotype displayed higher anti-PD-L1 mAb-mediated ADCC lysis of tumor cells than donors with a low-affinity genotype. Conclusion These results suggest that NK cells induce an ADCC response in combination with anti-PD-L1 mAbs, which helps promote ADCC antitumor activity against PD-L1-positive tumors. This study provides support for NK cell immunotherapy against high PD-L1-expressing tumors in combination with ADCC through anti-PD-L1 mAbs.

Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway

In bacteria, nascent proteins bear the pretranslationally generated N-terminal (Nt) formyl-methionine (fMet) residue. Nt-fMet of bacterial proteins is a degradation signal, termed fMet/N-degron. In contrast, proteins synthesized by cytosolic ribosomes of eukaryotes were presumed to bear unformylated Nt-Met. Here we found that the yeast formyltransferase Fmt1, although imported into mitochondria, could also produce Nt-formylated proteins in the cytosol. Nt-formylated proteins were strongly up-regulated in stationary phase or upon starvation for specific amino acids. This up-regulation strictly required the Gcn2 kinase, which phosphorylates Fmt1 and mediates its retention in the cytosol. We also found that the Nt-fMet residues of Nt-formylated proteins act as fMet/N-degrons, and identified the Psh1 ubiquitin ligase as the recognition component of this eukaryotic fMet/N-end rule pathway, which destroys Nt-formylated proteins

In vitro and in vivo assessments of an optimal polyblend composition of polycaprolactone/gelatin nanofibrous scaffolds for Achilles tendon tissue engineering

In this study, we manufactured various ratios of polycaprolactone (PCL)/gelatin (GE) highly aligned electrospun nanofibrous scaffolds (ENs) to investigate the effects of polymer ratio on tenogenic differentiation activity. For biological assessments, the cell proliferation rate was optimal in the PCL/GE (9:1) group. Interestingly, however, the tenogenic differentiation rate was best for the PCL/GE (7:3) group. From our outcomes, we established that a poly-blending mix of PCL/GE (7:3) is a promising ratio for tenogenic differentiation. Thus, our findings may provide for an effective mesh to promote tenogenic differentiation of ENs in future tendon tissue engineering applications.This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean government (MSIP&MOHW) (No. 2017M3A9E4048170)

Comparison of Endoscopic Submucosal Dissection With Endoscopic Mucosal Resection After Circumferential Precutting to Treat Gastric Adenomas ≤15 mm

Objectives Endoscopic submucosal dissection (ESD) is a widely used approach for the resection of superficial gastric neoplastic lesions. Endoscopic mucosal resection (EMR) is acceptable for lesions <10–15 mm in size. Herein, we compared the clinical outcomes of ESD with those of EMR after circumferential precutting (EMR-P) for gastric adenomas ≤15 mm. Methods We retrospectively analyzed the data of 213 patients with 228 gastric adenomas ≤15 mm in size who were treated endoscopically at a single tertiary hospital in Korea between November 2018 and October 2022. We evaluated the complete endoscopic resection rate, recurrence rate, procedurer-elated complications, and procedure time according to the procedure used. Results Among the 228 gastric adenomas, 49 were treated with EMR-P and 179 with ESD. The histological complete resection rate was higher in the ESD group than in the EMR-P group (87% vs. 57%, p<0.001). No significant between-group differences were observed in endoscopic en bloc resection rates (ESD vs. EMR-P, 96% vs. 90%; p=0.081). The procedure time was significantly shorter in the EMR-P group than in the ESD group (28.9±19.7 min vs. 8.8±5.9 min, p<0.001). The local recurrence rate in patients with histologically incomplete resection did not differ between the two groups (ESD vs. EMR-P, 8.7% vs. 9.5%; p=0.924). Conclusions For gastric adenomas ≤15 mm, EMR-P may be the preferable treatment method considering the en bloc resection rate, procedure time, and local recurrence rate. However, considering the complete resection rate, ESD is recommended as the treatment of choice for high-grade adenomas and early gastric cancer lesions

Developing evidence-based clinical imaging guidelines of justification for radiographic examination after dental implant installation

Abstract Background This study aimed to develop evidence-based clinical imaging guidelines to assess the proper implant location following implant surgery and identify potential complications during follow-up. Methods The guideline development process employed an adaptation methodology in accordance with the Korean clinical imaging guidelines (K-CIG). Core (Ovid-Medline, Ovid-Embase, National Guideline Clearinghouse, and Guideline International Network) and domestic databases (KoreaMed, KMbase, and KoMGI) were searched used to retrieve guidelines, and two reviewers analyzed the retrieved articles. The articles were included in this review using well-established inclusion criteria. Results Our online search identified 66 articles, of which 3 were selected for the development of the guidelines. Consequently, based on these three guidelines, we formulated distinct recommendations regarding the appropriate imaging modalities that should be used following implant placement. Conclusions Conventional imaging (e.g., periapical or panoramic radiography) should be the first choice for assessing the implant following its placement and osseointegration. The metal artifacts in Cone Beam Computed Tomography (CBCT) should be considered. However, CBCT is recommended for patients with sensory abnormalities following dental implant surgery to evaluate and identify the underlying cause of implant complications and to determine the appropriate treatment

AKAP12 Mediates Barrier Functions of Fibrotic Scars during CNS Repair

The repair process after CNS injury shows a well-organized cascade of three distinct stages: inflammation, new tissue formation, and remodeling. In the new tissue formation stage, various cells migrate and form the fibrotic scar surrounding the lesion site. The fibrotic scar is known as an obstacle for axonal regeneration in the remodeling stage. However, the role of the fibrotic scar in the new tissue formation stage remains largely unknown. We found that the number of A-kinase anchoring protein 12 (AKAP12)-positive cells in the fibrotic scar was increased over time, and the cells formed a structure which traps various immune cells. Furthermore, the AKAP12-positive cells strongly express junction proteins which enable the structure to function as a physical barrier. In in vivo validation, AKAP12 knock-out (KO) mice showed leakage from a lesion, resulting from an impaired structure with the loss of the junction complex. Consistently, focal brain injury in the AKAP12 KO mice led to extended inflammation and more severe tissue damage compared to the wild type (WT) mice. Accordingly, our results suggest that AKAP12-positive cells in the fibrotic scar may restrict excessive inflammation, demonstrating certain mechanisms that could underlie the beneficial actions of the fibrotic scar in the new tissue formation stage during the CNS repair process

Association of appendicular skeletal muscle mass with carotid intima-media thickness according to body mass index in Korean adults

OBJECTIVES The combined effects of obesity and appendicular skeletal muscle (ASM) on atherosclerosis, especially in middleaged populations, remain poorly understood. This cross-sectional study investigated the effects of ASM on carotid intima-media thickness (IMT) according to body mass index (BMI) in middle-aged Korean adults. METHODS Herein, 595 men and 1,274 women aged 30-64 years completed questionnaires and underwent health examinations as part of the Cardiovascular and Metabolic Disease Etiology Research Center cohort. ASM was measured via bioelectrical impedance analysis and adjusted for weight (ASM/Wt). IMT was assessed using B-mode ultrasonography; highest quartile of IMT was defined as gender-specific top quartile of the IMT values. Higher BMIs was defined as a BMI over 25.0 kg/m2 . RESULTS Compared to the highest ASM/Wt quartile, the lowest ASM/Wt quartile was significantly associated with highest quartile of IMT in men with lower BMIs (adjusted odds ratio [aOR], 2.78; 95% confidence interval [CI], 1.09 to 7.13), but not in those with higher BMIs (aOR, 0.59; 95% CI, 0.24 to 1.91). In women, there was no significant association of low skeletal muscle mass with highest quartile of IMT, regardless of BMI. CONCLUSIONS Low appendicular skeletal muscle mass is associated with carotid arterial wall thickening in men with lower BMIs, but not in men with higher BMIs. Our findings suggest that the risk of atherosclerosis may be low in middle-aged Korean men with appropriate body weight and skeletal muscle mass maintenance

Impaired Set-Shifting Ability in Patients with Eating Disorders, Which Is Not Moderated by Their Catechol-O-Methyltransferase Val158Met Genotype

The aim of this study was to examine the set-shifting ability in women with both anorexia nervosa (AN) and bulimia nervosa (BN) and to investigate whether it is contributed by the catechol-O-methyltransferase (COMT) Val158Met genotype. A total of 102 Korean participants-40 women with lifetime AN, 28 women with lifetime BN, and 34 healthy women of comparable age and intelligence quotient- were examined. A neuropsychological battery of tests was applied and blood samples were obtained for COMT Val158Met genotyping. Set-shifting impairments Trail Making Test (TMT, Part B) were found in patients with AN and BN, respectively. Furthermore, the eating disorders were also linked to deficits in attentional mechanisms (TMT, Part A) and motor skills (Finger Tapping Test). Finally, set-shifting and its link to eating disorders were not moderated by COMT Val158Met genotype

Transcriptional control of hydrogen peroxide homeostasis regulates ground tissue patterning in the Arabidopsis root

In multicellular organisms, including higher plants, asymmetric cell divisions (ACDs) play a crucial role in generating distinct cell types. The Arabidopsis root ground tissue initially has two layers: endodermis (inside) and cortex (outside). In the mature root, the endodermis undergoes additional ACDs to produce the endodermis itself and the middle cortex (MC), located between the endodermis and the pre-existing cortex. In the Arabidopsis root, gibberellic acid (GA) deficiency and hydrogen peroxide (H2O2) precociously induced more frequent ACDs in the endodermis for MC formation. Thus, these findings suggest that GA and H2O2 play roles in regulating the timing and extent of MC formation. However, details of the molecular interaction between GA signaling and H2O2 homeostasis remain elusive. In this study, we identified the PEROXIDASE 34 (PRX34) gene, which encodes a class III peroxidase, as a molecular link to elucidate the interconnected regulatory network involved in H2O2- and GA-mediated MC formation. Under normal conditions, prx34 showed a reduced frequency of MC formation, whereas the occurrence of MC in prx34 was restored to nearly WT levels in the presence of H2O2. Our results suggest that PRX34 plays a role in H2O2-mediated MC production. Furthermore, we provide evidence that SCARECROW-LIKE 3 (SCL3) regulates H2O2 homeostasis by controlling transcription of PRX34 during root ground tissue maturation. Taken together, our findings provide new insights into how H2O2 homeostasis is achieved by SCL3 to ensure correct radial tissue patterning in the Arabidopsis root