Postoperative Long-Term Monitoring of Mechanical Characteristics in Reconstructed Soft Tissues Using Biocompatible, Immune-Tolerant, and Wireless Electronic Sutures.

Accurate postoperative assessment of varying mechanical properties is crucial for customizing patient-specific treatments and optimizing rehabilitation strategies following Achilles tendon (AT) rupture and reconstruction surgery. This study introduces a wireless, chip-less, and immune-tolerant in vivo strain-sensing suture designed to continuously monitor mechanical stiffness variations in the reconstructed AT throughout the healing process. This innovative sensing suture integrates a standard medical suturing thread with a wireless fiber strain-sensing system, which incorporates a fiber strain sensor and a double-layered inductive coil for wireless readout. The winding design of Au nanoparticle-based fiber electrodes and a hollow core contribute to the fiber strain sensor's high sensitivity (factor of 6.2 and 15.1 pF for revised sensitivity), negligible hysteresis, and durability over 10,000 stretching cycles. To ensure biocompatibility and immune tolerance during extended in vivo periods, an antibiofouling lubricant layer was applied to the sensing suture. Using this sensing system, we successfully monitored the strain responses of the reconstructed AT in an in vivo porcine model. This facilitated the postoperative assessment of mechanical stiffness variations through a well-established analytical model during the healing period.

Postoperative Stability in Displaced Ankle Fractures With Concomitant Ligamentous Injuries.

Ankle instability, which can be attributed to either the deltoid or lateral ligamentous complex, may be both a cause and a consequence of ankle fractures. This study aimed to assess postoperative ankle instability in patients with displaced ankle fractures. A total of 54 patients with displaced ankle fractures were included. Malleolar fractures were surgically reduced and fixated, and if necessary, the syndesmosis was stabilized. Concomitant deltoid injuries were left unrepaired. Ankle stress radiographs were taken approximately 25.4 months after surgery, with a standard deviation of 20.5 months. Radiographic measurements included the tibiotalar tilt angle (TT) on varus stress view, anterior translation of the talus (AT) on the anterior drawer view, and the medial clear space (MC) and tibiotalar tilt angle on the valgus stress view. These measurements were compared between the injured and the noninjured contralateral ankle for all patients as well as in a subgroup of 19 patients with concomitant deltoid and syndesmosis injuries. There were no significant differences in Varus TT (p = .675, p = .394), AT (p = .516, p = .967), Valgus MC (p = .190, p = 0.498), and Valgus TT (p = .173, p = .442) between the injured and noninjured ankles in the whole group of patients as well as in the subgroup of patients with concomitant deltoid and syndesmosis injuries. Patients with displaced ankle fractures exhibited radiographically stable ankles postoperatively. Syndesmosis fixation without deltoid ligament repair is a viable treatment option for achieving ankle stability postoperatively in fractures with both ligament injuries.

Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via the type I interferon pathway in PD-L1-expressing head and neck cancer.

Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD-1) have been proven to be an effective first-line therapy against programmed cell death 1 ligand 1 (PD-L1; also known as CD274 molecule)-expressing head and neck squamous cell carcinoma (HNSCC) in recent KEYNOTE-048 trial. However, associated changes in the tumor microenvironment (TME) and underlying mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou oral cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in the TME, including vascular normalization. Furthermore, the antitumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2). The ICB-induced antitumorigenicity and TME normalization were alleviated by blocking the type I interferon pathway. In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the type I interferon pathway is indispensable in realizing the effects of ICBs. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against PD-L1-expressing HNSCC in the KEYNOTE-048 trial.

Redescription and molecular phylogeny of Trochilia sigmoides Dujardin, 1841 (Ciliophora, Cyrtophoria) collected from South Korea.

During a survey of Korean marine ciliates, Trochilia sigmoides, the type species of the genus Trochilia, was collected and examined using in vivo observation and protargol impregnation. Moreover, scanning electron microscopy and 18S rRNA gene sequencing have been applied for the first time to study this species. Morphologically, T. sigmoides is characterized by the small body size, the oval body outline, and the spiral dorsal ridges. The Korean population of T. sigmoides shows only minute differences to other populations reported in the literature, mainly in body size and the number of dorsal ridges. Phylogenetic analyses based on 18S rRNA gene sequences show that T. sigmoides and T. petrani are placed together with two members of the family Kyaroikeidae, causing the family Dysteriidae to be non-monophyletic. The present new data increase the knowledge about the morphology and phylogeny of the genus Trochilia and would assist in understanding the phylogenetic relationship between the free-living Dysteriidae and the parasitic Kyaroikeidae.

Explainable Model Using Shapley Additive Explanations Approach on Wound Infection after Wide Soft Tissue Sarcoma Resection: "Big Data" Analysis Based on Health Insurance Review and Assessment Service Hub.

Background and Objectives: Soft tissue sarcomas represent a heterogeneous group of malignant mesenchymal tissues. Despite their low prevalence, soft tissue sarcomas present clinical challenges for orthopedic surgeons owing to their aggressive nature, and perioperative wound infections. However, the low prevalence of soft tissue sarcomas has hindered the availability of large-scale studies. This study aimed to analyze wound infections after wide resection in patients with soft tissue sarcomas by employing big data analytics from the Hub of the Health Insurance Review and Assessment Service (HIRA). Materials and Methods: Patients who underwent wide excision of soft tissue sarcomas between 2010 and 2021 were included. Data were collected from the HIRA database of approximately 50 million individuals' information in the Republic of Korea. The data collected included demographic information, diagnoses, prescribed medications, and surgical procedures. Random forest has been used to analyze the major associated determinants. A total of 10,906 observations with complete data were divided into training and validation sets in an 80:20 ratio (8773 vs. 2193 cases). Random forest permutation importance was employed to identify the major predictors of infection and Shapley Additive Explanations (SHAP) values were derived to analyze the directions of associations with predictors. Results: A total of 10,969 patients who underwent wide excision of soft tissue sarcomas were included. Among the study population, 886 (8.08%) patients had post-operative infections requiring surgery. The overall transfusion rate for wide excision was 20.67% (2267 patients). Risk factors among the comorbidities of each patient with wound infection were analyzed and dependence plots of individual features were visualized. The transfusion dependence plot reveals a distinctive pattern, with SHAP values displaying a negative trend for individuals without blood transfusions and a positive trend for those who received blood transfusions, emphasizing the substantial impact of blood transfusions on the likelihood of wound infection. Conclusions: Using the machine learning random forest model and the SHAP values, the perioperative transfusion, male sex, old age, and low SES were important features of wound infection in soft-tissue sarcoma patients.

Dynamic Foot Pressure During Walking: A Potential Indicator of Bone Mineral Density.

BACKGROUND: Physical skeletal loading can affect the bone mineral density (BMD). This study investigated the association between BMD and dynamic foot pressure during gait. METHODS: A total of 104 patients (mean age, 62.6 ± 12.4 years; 23 male and 81 female) who underwent dual x-ray absorptiometry and pedobarography were included. BMD values of the lumbar spine, femoral neck, and total femur were assessed. The mean and maximum pressures were measured at the hallux, lesser toes, 1st metatarsal head, 2nd and 3rd metatarsal heads, 4th and 5th metatarsal heads, midfoot, medial heel, and lateral heel. Multivariable regression analysis was performed to identify factors significantly associated with BMD. RESULTS: The lumbar spine BMD was significantly associated with the mean pressure at the 4th and 5th metatarsal heads (p = 0.041, adjusted R 2 of model = 0.081). The femoral neck BMD was significantly associated with the maximum pressure at the 2nd and 3rd metatarsal heads (p = 0.002, adjusted R 2 = 0.213). The total femoral BMD also showed a significant association with the maximum pressure at the 2nd and 3rd metatarsal heads (p = 0.003, adjusted R 2 = 0.360). CONCLUSIONS: Foot plantar pressure during gait was significantly associated with BMD, and could potentially be used to predict the presence of osteoporosis. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Radiographic Evaluation of the Association between Foot Deformities and Ankle Medial Osteoarthritis.

Background: Foot deformities can cause abnormal biomechanics of the ankle joint and the development of osteoarthritis. It was hypothesized that foot deformities would be related to medial ankle osteoarthritis, and this study investigated this relationship using radiographic measurements. Methods: Seventy-six ankles of 76 patients (32 men and 44 women; mean age, 69.0 years) with medial ankle osteoarthritis were included. Eleven radiographic measurements evaluated ankle joint orientation (tibial plafond inclination [TPI], medial distal tibial angle [MDTA], and anterior distal tibial angle [ADTA]), ankle joint incongruency (tibiotalar tilt [TT]), foot deformities (lateral talo-first metatarsal angle [Lat talo-1MT], anteroposterior talo-first metatarsal angle [AP talo-1MT], and talonavicular coverage), talar body migration (medial talar center migration [MTCM] and anterior talar center migration [ATCM]), internal rotation (IR) of the talus, and mechanical tibiofemoral angle. All were statistically analyzed using Pearson's correlation coefficients and regression analyses. Results: Ankle joint orientation to the ground (TPI, p = 0.002), increased foot arch (Lat talo-1MT, p < 0.001), and IR of the talus (p = 0.001) were significantly associated with ankle joint incongruency (TT) in linear regression analysis. Ankle joint incongruency (TT, p = 0.003), medial talar body migration (MTCM, p = 0.042), and increased foot arch (Lat talo-1MT, p = 0.022) were significantly associated with IR of the talus in the binary logistic regression analysis. MTCM was significantly correlated with TPI (r = 0.251, p = 0.029), TT (r = 0.269, p = 0.019), MDTA (r = 0.359, p = 0.001), ATCM (r = -0.522, p < 0.001), and AP talo-1MT (r = 0.296, p = 0.015). ATCM was significantly correlated with TPI (r = -0.253, p = 0.027), ADTA (r = 0.349, p = 0.002), and Lat talo-1MT (r = -0.344, p = 0.002). Conclusions: Ankle joint orientation, foot deformities, and talar rotation were associated with ankle joint incongruency in medial ankle osteoarthritis when evaluated radiographically. These findings need to be considered during surgical treatment for medial ankle osteoarthritis. However, the biomechanical significance of these radiographic measurements requires further investigation.

Natural course of talar avascular necrosis during short-term follow-up and factors associated with Disease progression.

BACKGROUND: This retrospective cohort study aimed to investigate the natural history of talar avascular necrosis (AVN) during short-term outpatient follow-up and to identify the risk factors for progression to collapse and arthritic changes. METHODS: Thirty-four cases of talar AVN from 34 patients (15 males, 19 females) were included. The mean age of the patients was 48.9 years (SD 16.0 years) and the mean follow-up period was 39.5 months (SD 42.0 months). The patients were divided into two groups i.e., progression and non-progression groups. The progression group consisted of those who showed aggravation of the Ficat stage during the follow-up period or advanced arthritis of the ankle joint (Ficat stage 4) at presentation. Demographic data and information regarding BMI, medical comorbidities, trauma history, bilaterality, and location of the lesion (shoulder vs. non-shoulder lesions) were collected. Following the univariate analysis, a binary logistic regression analysis was performed. RESULTS: The location of the talar AVN was the only significant factor (p = 0.047) associated with disease progression. A total of 14.3% (2 of 14) of the central (non-shoulder) talar AVN lesions showed progression, while 50% (10 of 20) of shoulder lesions aggravated during follow-up. Age, sex, bilaterality, medical comorbidities, and trauma history were not associated with progressive talar collapse or subsequent arthritic changes in talar AVN. CONCLUSIONS: Conservative treatment should be considered for a central lesion of the talar AVN because it tends to remain stable without progression. A more comprehensive study with a larger study population is required to establish the surgical indications for talar AVN. LEVEL OF EVIDENCE: Prognostic level III.

Comprehensive profiling of DNA methylation in Korean patients with colorectal cancer.

Alterations in DNA methylation play an important pathophysiological role in the development and progression of colorectal cancer. We comprehensively profiled DNA methylation alterations in 165 Korean patients with colorectal cancer (CRC), and conducted an in-depth investigation of cancer-specific methylation patterns. Our analysis of the tumor samples revealed a significant presence of hypomethylated probes, primarily within the gene body regions; few hypermethylated sites were observed, which were mostly enriched in promoter-like and CpG island regions. The CpG Island Methylator PhenotypeHigh (CIMP-H) exhibited notable enrichment of microsatellite instability-high (MSI-H). Additionally, our findings indicated a significant correlation between methylation of the MLH1 gene and MSI-H status. Furthermore, we found that the CIMP-H had a higher tendency to affect the right-side of the colon tissues and was slightly more prevalent among older patients. Through our methylome profile analysis, we successfully verified the thylation patterns and clinical characteristics of Korean patients with CRC. This valuable dataset lays a strong foundation for exploring novel molecular insights and potential therapeutic targets for the treatment of CRC. [BMB Reports 2024; 57(2): 110-115].

Morphology, morphogenesis, and molecular phylogeny of Aspidisca koreana n. sp. (Ciliophora, Euplotida) from South Korea.

The morphology, morphogenesis, and molecular phylogeny of a new ciliate, Aspidisca koreana n. sp., discovered in the eastern coast of South Korea, were investigated. The morphological description is based on the observation of living cells, 4'-6-diamidino-2-phenylindole (DAPI) and silver-stained specimens (e.g., protargol, silver nitrate), and scanning electron micrographs. The new species is characterized by having a small body size (17-25 × 15-18 µm in vivo), a distinct peristomial spur on the posterior portion of left margin, seven frontoventral cirri in "polystyla-arrangement", and the arrangement of the anterior portion of adoral zone of membranelles, i.e., anteriormost membranelle is distinctly separated from the other three membranelles. The morphogenesis follows the typical pattern of this genus. Phylogenetic analyses, using the 18S rDNA sequence, also support the establishment of a new species.

Effect of flatfoot correction on the ankle joint following lateral column lengthening: A radiographic evaluation.

OBJECTIVES: The effects of foot deformities and corrections on the ankle joint without osteoarthritis has received little attention. This study aimed to investigate the effect of flatfoot correction on the ankle joint of patients without osteoarthritis. METHODS: Thirty-five patients (24 men and 11 women; mean age 17.5 years) who underwent lateral column lengthening for flatfoot deformities were included. The mean postoperative follow-up period was 20.5 months (standard deviation [SD]: 15.7 months). Radiographic indices were measured pre- and postoperatively, including anteroposterior (AP) and lateral talo-first metatarsal angles, naviculocuboid overlap, position of the articulating talar surface, and lateral talar center migration. Postoperative changes in the radiographic indices were statistically analyzed. RESULTS: There was significant postoperative improvement in flatfoot deformity in terms of AP and lateral talo-first metatarsal angles (p<0.001 and p<0.001, respectively) and naviculocuboid overlap (p<0.001). On lateral radiographs, the talar articulating surface dorsiflexed by 7.3% (p<0.001), and the center of the talar body shifted anteriorly by 0.85 mm (p<0.001) postoperatively. CONCLUSIONS: Flatfoot correction using lateral column and Achilles tendon lengthening caused dorsiflexion and an anterior shift of the articular talar body in patients without osteoarthritis. Correction of flatfoot deformity might affect the articular contact area at the ankle joint. The biomechanical effects of this change need to be investigated further.

Supplementary Effects of Allium hookeri Extract on Glucose Tolerance in Prediabetic Subjects and C57BL/KsJ-db/db Mice.

Allium hookeri (AH) has been used as a nutritional and medicinal food in Asia for many years. Our previous studies have described its anti-diabetic, anti-obesity, and anti-inflammatory activities in animal models and prediabetes. This study investigated whether AH could improve glycemia by modulating insulin secretion in prediabetic subjects through an in-depth study. Eighty prediabetic subjects (100 ≤ fasting plasma glucose < 140 mg/dL) were randomly assigned to a placebo (n = 40) group or an ethanol AH extract (500 mg/day, n = 40) group for 12 weeks. Dietary intake and physical activity, blood glucose (an oral glucose tolerance test for 120 min), insulin (insulin response to oral glucose for 120 min), area under the curve (AUC) of glucose or insulin after oral glucose intake, insulin sensitivity markers, C-peptide, adiponectin, glycated hemoglobin A1c (HbA1c) levels, hematological tests (WBC, RBC, hemoglobin, hematocrit, and platelet count), blood biochemical parameters (ALP, AST, total bilirubin, total protein, albumin, gamma-GT, BUN, creatinine, LD, CK, and hs-CRP), and urine parameters (specific gravity and pH) were examined at both baseline and 12 weeks after supplementation with placebo or AH capsules. Fifty-eight participants (placebo group: 20 men and 10 women; AH group: 13 men and 15 women) completed the study. AH supplementation moderately reduced postprandial blood glucose at 60 min (-6.14 mg/dL, p = 0.061), postprandial insulin levels at 90 min (-16.69 µU/mL, p = 0.017), the glucose AUC at 90 min (-412.52 mg*min/dL, p = 0.021), as well as the insulin AUC at 90 min (-978.77 µU*min/mL, p = 0.021) and 120 min (-1426.41 µU*min/mL, p = 0.015) when compared with the placebo group. However, there were no effects of AH on dietary intake and physical activity; HOMA index; HbAlc; C-peptide; or adiponectin, hematological-, blood biochemical-, and urinary markers. To confirm the effects of AH extract on blood glucose insulin sensitivity, C57BL/6J or C57BL/KsJ-db/db mice were used (n = 8/group). Body weight, fasting plasma glucose level, lipid profiles, liver and renal function, pancreatic histology, and insulin immunoreactivity were assessed. In the diabetic db/db mice, hyperglycemia, which was accompanied by an increase in insulin secretion in diabetic mice, was significantly reduced by AH treatment, resulting in the alleviation of ß-cell overcompensation and insulin resistance. We confirmed that AH supplementation can effectively control blood glucose and insulin levels by improving insulin sensitivity and may be a potential agent for glycemic control in subjects with prediabetes and type 2 diabetes mellitus.

Efficacy and safety of diacerein and celecoxib combination therapy for knee osteoarthritis: A double-blind, randomized, placebo-controlled prospective study.

BACKGROUND: Osteoarthritis is a degenerative disease with a growing burden in South Korea. Corresponding drugs are commonly used for pain relief and joint function improvement. Specifically, symptomatic slow-acting drugs for osteoarthritis are frequently used, with diacerein being the most common symptomatic slow-acting drugs for osteoarthritis in South Korea. In this study, we evaluated the efficacy and safety of diacerein and celecoxib combination therapy in patients with osteoarthritis. METHODS: A total of 71 subjects were randomly assigned to group 1 (diacerein and celecoxib), 2 (diacerein and placebo), or 3 (celecoxib and placebo). The primary outcome measure was the change in the visual analog scale (VAS) score 12 weeks after treatment. RESULTS: The combination therapy group exhibited a significant decrease in the VAS score, alongside the other control monotherapy groups. Although there was no significant difference between the groups, the combination therapy group exhibited a greater decrease in the absolute value of the VAS score than the other groups. Four weeks after treatment, the combination therapy group showed significantly higher improvement in the stiffness and physical function categories of the Western Ontario and McMaster Universities Osteoarthritis Index than the other groups. Additionally, no serious adverse events occurred following combination therapy, with most adverse events being mild and resolving without specific treatment. CONCLUSIONS: Diacerein and celecoxib combination therapy is as safe and effective as corresponding monotherapies. A relatively early improvement in stiffness and physical function following treatment with this combination therapy indicates that physicians should consider this for the early-stage treatment of patients with symptomatic osteoarthritis.

CCIDB: a manually curated cell-cell interaction database with cell context information.

Cell-cell interaction (CCI) is a crucial event in the development and function of multicellular organisms. The development of CCI databases is beneficial for researchers who want to analyze single-cell sequencing data or study CCI through molecular experiments. CCIs are known to act differently according to cellular and biological contexts such as cell types, gene mutations or disease status; however, previous CCI databases do not completely provide this contextual information pertaining to CCIs. We constructed a cell-cell interaction database (CCIDB) containing the biological and clinical contexts involved in each interaction. To build a database of cellular and tissue contexts, we collected 38 types of context features, which were categorized into seven categories, including 'interaction', 'cell type', 'cofactor', 'effector', 'phenotype', 'pathology' and 'reference'. CCIs were manually retrieved from 272 studies published recently (less than 6 years ago). In the current version of CCIDB, 520 CCIs and their 38 context features have been manually collected and curated by biodata engineers. We suggest that CCIDB is a manually curated CCI resource that is highly useful, especially for analyzing context-dependent alterations in CCIs. Database URL https://ccidb.sysmed.kr/.

Intravitreal Administration of Retinal Organoids-Derived Exosomes Alleviates Photoreceptor Degeneration in Royal College of Surgeons Rats by Targeting the Mitogen-Activated Protein Kinase Pathway.

Increasing evidence suggests that exosomes are involved in retinal cell degeneration, including their insufficient release; hence, they have become important indicators of retinopathies. The exosomal microRNA (miRNA), in particular, play important roles in regulating ocular and retinal cell functions, including photoreceptor maturation, maintenance, and visual function. Here, we generated retinal organoids (ROs) from human induced pluripotent stem cells that differentiated in a conditioned medium for 60 days, after which exosomes were extracted from ROs (Exo-ROs). Subsequently, we intravitreally injected the Exo-RO solution into the eyes of the Royal College of Surgeons (RCS) rats. Intravitreal Exo-RO administration reduced photoreceptor apoptosis, prevented outer nuclear layer thinning, and preserved visual function in RCS rats. RNA sequencing and miRNA profiling showed that exosomal miRNAs are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, the expression of MAPK-related genes and proteins was significantly decreased in the Exo-RO-treated group. These results suggest that Exo-ROs may be a potentially novel strategy for delaying retinal degeneration by targeting the MAPK signaling pathway.

Radiographic Measurements Associated With Ankle Power Generation During Gait in Patients With Cerebral Palsy.

BACKGROUND: Pes planovalgus (PV) deformity accounts for lever arm dysfunction and compromises gait in patients with cerebral palsy (CP). However, the association between ankle power generation and radiographic indices is not yet understood. We aimed to investigate the association between ankle power and radiographic indices during gait in patients with CP concomitant with PV deformity. METHODS: Patients older than 14 years with ambulatory CP and PV deformity were included. All the patients underwent 3-dimensional gait analysis and weight-bearing foot radiography. Gait data were collected, including foot progression angle, tibial rotation, hip rotation, and ankle power generation. Radiographic measurements included anteroposterior (AP) talo-first metatarsal angle, lateral talo-first metatarsal angle, and hindfoot angle. A linear mixed-effects model was performed to identify significant radiographic indices associated with ankle power generation. RESULTS: Thirty-one limbs from 15 patients with spastic diplegia and 6 with spastic hemiplegia were included. Statistical analysis demonstrated that ankle power generation was significantly correlated with the CP type ( P =0.0068) and AP talo-1 st metatarsal angle ( P =0.0230). CONCLUSION: Ankle power generation was significantly associated with the AP talo-first metatarsal angle. Surgeons might need to pay attention to correcting forefoot abduction to restore ankle power when planning surgeries for pes PV deformities in patients with CP. LEVEL OF EVIDENCE: Prognostic Level III.

Antioxidant and Immune Stimulating Effects of Allium cepa Skin in the RAW 264.7 Cells and in the C57BL/6 Mouse Immunosuppressed by Cyclophosphamide.

Allium cepa L. (onion) has been reported to have various pharmacological effects, such as preventing heart disease, and improving antimicrobial activity and immunological effects. The Republic of Korea produced 1,195,563 tons of onions (2022). The flesh of onion is used as food while the onion skin (OS) is thrown away as an agro-food by-product and is considered to induce environmental pollution. Thus, we hypothesize that increasing usage of OS as functional food material could help protect from the environment pollution. The antioxidant effects and immune-enhancing effects of OS were evaluated as functional activities of OS. In this study, OS showed high 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities and xanthine oxidase (XO) inhibitory activity. The antioxidant activities increased in a dose-dependent manner. The IC50 values of DPPH, ABTS radical scavenging activity, and XO inhibitory activity were 954.9 µg/mL, 28.0 µg/mL, and 10.7 µg/mL, respectively. Superoxide dismutase and catalase activities of OS in RAW 264.7 cells were higher than those of the media control. There was no cytotoxicity of OS found in RAW 264.7 cells. Nitric oxide and cytokines (IL-1ß, IL-6, IFN-γ, and TNF-α) concentrations in RAW 264.7 cells significantly increased in a dose dependent manner. Immune-stimulating effects of OS were evaluated in immunosuppressed mice induced by cyclophosphamide. White blood cell count and the B cell proliferation of splenocytes were higher in OS100 (OS extract 100 mg/kg body weight) and OS200 (OS extract 200 mg/kg body weight) groups than in the negative control (NC) group. Serum IgG and cytokine (IL-1ß and IFN-γ) levels were also higher in OS100 and OS200 groups than in the NC group. OS treatment increased NK cell activity compared with the NC group. The results suggested that OS can improve antioxidant and immune stimulating effects. The use of OS as functional supplement can reduce the agro-food by-product and it may contribute to carbon neutrality.

A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal enzyme in the Toll-like receptor (TLR)/MYD88 dependent signaling pathway, which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in vivo. In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs. In addition, KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.

Single-cell transcriptome profiling of the stepwise progression of head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) undergoes stepwise progression from normal tissues to precancerous leukoplakia, primary HNSCC, and metastasized tumors. To delineate the heterogeneity of tumor cells and their interactions during the progression of HNSCC, we employ single-cell RNA-seq profiling for normal to metastasized tumors. We can identify the carcinoma in situ cells in leukoplakia lesions that are not detected by pathological examination. In addition, we identify the cell type subsets of the Galectin 7B (LGALS7B)-expressing malignant cells and CXCL8-expressing fibroblasts, demonstrating that their abundance in tumor tissue is associated with unfavorable prognostic outcomes. We also demonstrate the interdependent ligand-receptor interaction of COL1A1 and CD44 between fibroblasts and malignant cells, facilitating HNSCC progression. Furthermore, we report that the regulatory T cells in leukoplakia and HNSCC tissues express LAIR2, providing a favorable environment for tumor growth. Taken together, our results update the pathobiological insights into cell-cell interactions during the stepwise progression of HNSCCs.

In vitro and in vivo phototoxicity on gastric mucosa induced by methylene blue.

Background: Methylene blue (MB) is used endoscopically to demarcate tumors and as a photosensitizer in photodynamic therapy (PDT). However, there are few in vivo studies about its toxicity in healthy stomach tissue. We performed sequential in vitro and in vivo analyses of MB-induced phototoxicity. Methods: We performed in vitro experiments using the AGS human gastric cancer cell line treated with light-emitting diode (LED) irradiation (3.6 J/cm2) and MB. Cytotoxicity was evaluated using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. In vivo toxicity was evaluated in the stomach of beagles using the same dose of fiber-optic LED via gastroscopy, after spraying 0.1% and 0.5% MB solutions. Stomach tissue was also evaluated using the TUNEL assay. Results: In vitro, increased concentrations of MB led to higher TUNEL scores. However, cell viability was significantly lower after MB plus LED irradiation than after treatment with MB alone (P < 0.001). In vivo, the TUNEL score was highest immediately after treatment with 0.1% or 0.5% MB plus light irradiation, and the score was significantly higher in the LED illumination plus MB group than in the control group (P < 0.05). The elevated TUNEL score was maintained for 3 days in the MB plus light irradiation group but returned to normal levels on day 10. Conclusions: : Endoscopic light application with MB 0.5% concentration to the stomach may be regarded as a safe procedure despite some DNA injuries in the early period.