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.

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.

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].

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.

Antioxidation and anti-inflammatory effects of gamma-irradiated silk sericin and fibroin in H2O2-induced HaCaT Cell.

Oxidative stress in skin cells can induce the formation of reactive oxygen species (ROS), which are critical for pathogenic processes such as immunosuppression, inflammation, and skin aging. In this study, we confirmed improvements from gamma-irradiated silk sericin (I-sericin) and gamma-irradiated silk fibroin (I-fibroin) to skin cells damaged by oxidative stress. We found that I-sericin and I-fibroin effectively attenuated oxidative stress-induced ROS generation and decreased oxidative stress-induced inflammatory factors COX-2, iNOS, tumor necrosis factor-α, and interleukin-1ß compared to the use of non-irradiated sericin or fibroin. I-sericin and I-fibroin effects were balanced by competition with skin regenerative protein factors reacting to oxidative stress. Taken together, our results indicated that, compared to non-irradiated sericin or fibroin, I-sericin, and I-fibroin had anti-oxidation and anti-inflammation activity and protective effects against skin cell damage from oxidative stress. Therefore, gamma-irradiation may be useful in the development of cosmetics to maintain skin health.

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.

Age, Body Mass Index, and Spur Size Associated with Patients' Symptoms in Plantar Fasciitis.

Background: Plantar fasciitis is a common cause of heel pain affecting 10% of the general population. This study aimed to investigate the specific symptoms in patients with plantar fasciitis using the Foot and Ankle Outcome Score (FAOS) questionnaire and their relationship with demographic and radiographic factors. Methods: We retrospectively analyzed 73 consecutive patients (mean age, 53.8 ± 10.0 years; 20 men and 53 women) with plantar fasciitis who had visited our foot and ankle clinic and undergone weight-bearing foot X-ray examinations. Their demographic data, anteroposterior and lateral talo-first metatarsal angles, intermetatarsal and hallux valgus angles, and responses to the FAOS questionnaire were recorded. Results: The quality-of-life subscale showed the lowest score of all FAOS subscales. Age was significantly correlated with quality of life (r = 0.297, p = 0.011), and body mass index was correlated with the function in sports and recreational activities (r = -0.251, p = 0.032). Age and body mass index were statistically significantly correlated with calcaneal spur size (r = 0.274, p = 0.027 and r = 0.324, p = 0.008, respectively). The calcaneal spur size was significantly correlated with pain (r = -0.348, p = 0.004), function in daily living (r = -0.410, p = 0.001), and function in sports and recreational activities (r = -0.439, p < 0.001). Conclusions: Demographic factors were associated with specific symptoms in patients with plantar fasciitis. Calcaneal spur size was the only radiographic parameter correlated with symptoms. These findings help communicate with patients, set appropriate treatment goals, and evaluate treatment effectiveness.

CGV: Cancer Genome Viewer, a web service for integrative cancer genome and pharmacogenomic data analysis.

MOTIVATION: Multi-omic profiling data, such as The Cancer Genome Atlas and pharmacogenomic data, facilitate research into cancer mechanisms and drug development. However, it is not easy for researchers to connect, integrate and analyze huge and heterogeneous data, which is a major obstacle to the utilization of cancer genomic data. RESULTS: We developed Cancer Genome Viewer (CGV), a user-friendly web service that provides functions to integrate and visualize cancer genome data and pharmacogenomic data. Users can easily select and customize the samples to be analyzed with the pre-defined selection options for patients' clinic-pathological features from multiple datasets. Using the customized dataset, users can perform subsequent data analyses comprehensively, including gene set analysis, clustering or survival analysis. CGV also provides pre-calculated drug response scores from pharmacogenomic data, which may facilitate the discovery of new cancer targets and therapeutics. AVAILABILITY AND IMPLEMENTATION: CGV web service is implemented with the R Shiny application at http://cgv.sysmed.kr and the source code is freely available at https://git.sysmed.kr/sysmed_public/cgv. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Intrasubject Radiographic Progression of Hallux Valgus Deformity in Patients With and Without Metatarsus Adductus: Bilateral Asymmetric Hallux Valgus Deformity.

This study was to analyze intrasubject radiographic progression of the hallux valgus deformity by comparing the mildly and severely affected sides in patients with bilateral asymmetric hallux valgus in the whole group as well as the metatarsus adductus and the nonmetatarsus adductus subgroups. A total of 186 patients with bilateral asymmetrical hallux valgus deformity with a difference of 5° or greater in the hallux valgus angle were included, and 11 radiographic measurements were analyzed. The radiographic differences between the mildly and severely affected sides were compared. Correlation between the changes in the hallux valgus angle and those in other measurements was analyzed, and multiple regression analyses were performed. The anteroposterior talo-second metatarsal angle showed no significant difference between the mildly and severely affected sides. Changes in the intermetatarsal angle and sesamoid rotation angle were significantly associated with the progression of hallux valgus angle in the whole group as well as the nonmetatarsus adductus subgroup. Change in the intermetatarsal angle (p = .006) was the significant factor associated with the progression of hallux valgus angle in the metatarsus adductus subgroup. The anteroposterior talo-second metatarsal angle might be useful in evaluating the overall foot shape in the hallux valgus deformity. Progression of the hallux valgus deformity might be pathophysiologically different between those with and without metatarsus adductus.

USO1 isoforms differentially promote liver cancer progression by dysregulating the ER-Golgi network.

Alternative splicing of RNA transcripts plays an important role in cancer development and progression. Recent advances in RNA-seq technology have made it possible to identify alternately spliced events in various types of cancer; however, research on hepatocellular carcinoma (HCC) is still limited. Here, by performing RNA-seq profiling of HCC transcripts at isoform level, we identified tumor-specific and molecular subtype-dependent expression of the USO1 isoforms, which we designated as a normal form USO1-N (XM_001290049) and a tumor form USO1-T (NM_003715). The expression of USO1-T, but not USO1-N, was associated with worse prognostic outcomes of HCC patients. We confirmed that the expression of USO1-T promoted an aggressive phenotype of HCC, both in vitro and in vivo. In addition, structural modeling analyses revealed that USO1-T lacks an ARM10 loop encoded by exon 15, which may weaken the dimerization of USO1 and its tethering to GM130. We demonstrated that USO1-T ensured unstacking of the Golgi and accelerated the vesicles trafficking from endoplasmic reticulum (ER) to Golgi and plasma membrane in multiple liver cancer cells. ERK and GRASP65 were found to be involved in the USO1-T-mediated Golgi dysfunction. Conclusively, we provide new mechanophysical insights into the USO1 isoforms that differentially regulate the ER-Golgi network, promoting the heterogeneous HCC progression.

TPRG1-AS1 induces RBM24 expression and inhibits liver cancer progression by sponging miR-4691-5p and miR-3659.

BACKGROUND & AIMS: Noncoding RNAs (ncRNAs) play critical roles in hepatocellular carcinoma (HCC) progression. Here, by performing RNA-sequencing (RNA-Seq) profiling, we sought to identify novel ncRNAs that potentially drive the heterogeneous progression of liver cancers. METHODS: RNA-Seq profiles were obtained from 68 HCC specimens and 10 samples of adjacent non-tumour liver tissues. The functional significance of the potential driver ncRNAs was evaluated by cell experiments. RESULTS: TPRG1-AS1 was identified as a potential driver noncoding RNA that promotes heterogeneous liver cancer progression. TPRG1-AS1 induced tumour suppressor RNA-binding motif protein 24 (RBM24), suppressing tumour growth by activating apoptotic tumour cell death. In addition, we report that TPRG1-AS1 acts as a competing endogenous RNA (ceRNA) for RBM24, sponging miR-4691-5p and miR-3659 to interfere with their binding to RBM24. CONCLUSIONS: We suggest that TPRG1-AS1 is a novel ceRNA sponging miR-4691-5p and miR-3659, resulting in RBM24 expression and suppression of liver cancer growth. Our results provide new insights into the functions of ncRNAs in heterogeneous HCC progression.

MLH1 single-nucleotide variant in circulating tumor DNA predicts overall survival of patients with hepatocellular carcinoma.

Liquid biopsy can provide a strong basis for precision medicine. We aimed to identify novel single-nucleotide variants (SNVs) in circulating tumor DNA (ctDNA) in patients with hepatocellular carcinoma (HCC). Deep sequencing of plasma-derived ctDNA from 59 patients with HCC was performed using a panel of 2924 SNVs in 69 genes. In 55.9% of the patients, at least one somatic mutation was detected. Among 25 SNVs in 12 genes, four frequently observed SNVs, MLH1 (13%), STK11 (13%), PTEN (9%), and CTNNB1 (4%), were validated using droplet digital polymerase chain reaction with ctDNA from 62 patients with HCC. Three candidate SNVs were detected in 35.5% of the patients, with a frequency of 19% for MLH1 chr3:37025749T>A, 11% for STK11 chr19:1223126C>G, and 8% for PTEN chr10:87864461C>G. The MLH1 and STK11 SNVs were also confirmed in HCC tissues. The presence of the MLH1 SNV, in combination with an increased ctDNA level, predicted poor overall survival among 107 patients. MLH1 chr3:37025749T>A SNV detection in ctDNA is feasible, and thus, ctDNA can be used to detect somatic mutations in HCC. Furthermore, the presence or absence of the MLH1 SNV in ctDNA, combined with the ctDNA level, can predict the prognosis of patients with HCC.

PCAF-Mediated Histone Acetylation Promotes Replication Fork Degradation by MRE11 and EXO1 in BRCA-Deficient Cells.

Stabilization of stalled replication forks is a prominent mechanism of PARP (Poly(ADP-ribose) Polymerase) inhibitor (PARPi) resistance in BRCA-deficient tumors. Epigenetic mechanisms of replication fork stability are emerging but remain poorly understood. Here, we report the histone acetyltransferase PCAF (p300/CBP-associated) as a fork-associated protein that promotes fork degradation in BRCA-deficient cells by acetylating H4K8 at stalled replication forks, which recruits MRE11 and EXO1. A H4K8ac binding domain within MRE11/EXO1 is required for their recruitment to stalled forks. Low PCAF levels, which we identify in a subset of BRCA2-deficient tumors, stabilize stalled forks, resulting in PARPi resistance in BRCA-deficient cells. Furthermore, PCAF activity is tightly regulated by ATR (ataxia telangiectasia and Rad3-related), which phosphorylates PCAF on serine 264 (S264) to limit its association and activity at stalled forks. Our results reveal PCAF and histone acetylation as critical regulators of fork stability and PARPi responses in BRCA-deficient cells, which provides key insights into targeting BRCA-deficient tumors and identifying epigenetic modulators of chemotherapeutic responses.

Transcriptomic analysis of the effect of (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl) prop-2-en-1-one (DPP23) on reactive oxygen species generation in MIA PaCa-2 pancreatic cancer cells.

BACKGROUND: Reactive oxygen species (ROS) generation specifically in cancer cells may be a promising strategy for their selective killing. The synthetic chalcone derivative (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP23) exerts antitumor activity through ROS-mediated apoptosis in cancer cells but not in healthy cells. However, the mechanism underlying ROS generation by DPP23 remains unknown. OBJECTIVE: The current study aims to identify possible DPP23 target genes responsible for ROS generation through the mining of microarray data stored in NCBI's Gene Expression Omnibus (GEO). METHODS: A comprehensive expression profile of genes modulated by DPP23 was examined by gene ontology analysis. DPP23-modulated genes in Mia-PaCa2 pancreatic cells were validated by reverse transcription-PCR. RESULTS: Multiple genes were up and downregulated by DPP23 treatment in MiaPaCa2 pancreatic cancer cells. Genes with absolute fold-change (FC) of > 2 were selected as the cut-off criteria and grouped into 10 clusters to analyze expression patterns systematically. We observed that genes with increased expression at 6 h were significantly affected by ROS increase, unfolded protein response, and cell death. Expression of 13 genes involved in glutathione metabolism, including CHAC1, GCLC, G6PD, GSTO2, GSTA5, GSTM2, GSR, GPX3/6/8, GGT1, PGD, ATF4, and NAT8B, are modulated by DPP23. Of these, CHAC1 was most highly upregulated upon DPP23 treatment. CONCLUSION: DPP23 alters global gene expression associated with multiple cellular responses, including oxidative stress and apoptosis. We found that DPP23 may induce GSH depletion through modulation of gene expression, which is especially involved in glutathione metabolism. Of these, CHAC1 emerged as the most prominent candidate for DPP23 as it was the most responsive to DPP23 treatment.