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Abstract The asymmetric division of stem cells permits the maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows inspection of the role of the stem cell niche to provide specific insights into essential developmental phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with low hardness, as the size of the apical bud was decreased and preameloblasts were shifted to the apical side, resulting in amelogenesis imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis was accelerated with Wnt signal downregulation. Distal-Less Homeobox 3 (DLX3), a critical factor in tooth amelogenesis, is considered to be responsible for the development of amelogenesis imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization site (NLS) that promotes the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role for MAST4 as a critical regulator of the entire amelogenesis process through its control of Wnt signaling and DLX3 transcriptional activity.

With the increasing obesity rates, many studies on obesity prevention and management have been implemented. However, few studies focused on obesity in adulthood and different perceptions of obesity between life cycles. Thus, this study aimed to investigate the demand for customized obesity prevention and management (OPM) strategies across adult age groups. Focus group interviews were conducted to gather insights from three age groups: young adults (20-34 years), middle-aged adults (35-49 years), and seniors (50-64 years). A total of 17 participants took part in the study, with 5 participants in Group 1, 6 participants in Group 2, and 6 participants in Group 3. Thematic analysis and the use of NetMiner version 4.4.3 facilitated data categorization and scrutiny. The study employed qualitative methods to explore perceptions of obesity and preferences for personalized OPM strategies among participants. Diverse perspectives on obesity as a health threat were found among the age groups. While all stressed the importance of personalized OPM, preferences for strategies varied. Diet and exercise combination emerged as a common preference. This study highlighted the need for customized OPM approaches aligned with age-specific preferences.

Objective To compare unilateral extrapedicular vertebroplasty (UEV) and bilateral transpedicular vertebroplasty (BTV) by quantitatively calculating the structural changes of fractured vertebral body after percutaneous vertebroplasty (PVP) using 3-dimensional voxel-based morphometry (VBM). Methods We calculated bone cement volume (BCV); vertebral body volume (VBV); leaked intradiscal BCV; and spatial, symmetric, and even bone cement distribution (BCD) in and out of 222 vertebral bodies treated with 2 different PVPs using VBM and evaluated the incidence of subsequent vertebral compression fracture (SVCF). Statistical analyses were conducted to compare values between the 2 different PVPs. Results Relative BCV, which is a potential risk factor for SVCF, was higher in the BTV group based on the data using VBM (0.22±0.03 vs. 0.29±0.03; p

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most lethal type of cancer and the third leading cause of cancer death with the lowest 5-year survival rate. Heterogeneity, difficulty in diagnosis, and rapid metastatic progression are the causes of high mortality in pancreatic cancer. Recent studies have shown that Protein arginine methyltransferase 5 (PRMT5) is overexpressed in pancreatic cancers, and these patients have a worse prognosis. Recently, PRMT5 as an anti-cancer target has gained considerable interest. In this study, we investigated whether inhibition of PRMT5 activity was synergistic with blockade of TGF-β1 signaling, which plays an important role in the construction of the desmoplastic matrix in pancreatic cancer and induces therapeutic vulnerability. Compared with T1-44, a selective inhibitor of PRMT5 activity, the combination of T1-44 with the TGF-β1 signaling inhibitor Vactosertib significantly reduced tumor size and surrounding tissue invasion and significantly improved long-term survival. RNA sequencing analysis of mouse tumors revealed that the combination of T1-44 and Vactosertib significantly altered the expression of genes involved in cancer progression, such as cell migration, extracellular matrix, and apoptotic processes. In particular, the expression of Btg2, known as a tumor suppressor factor in various cancers, was markedly induced by combination treatment. Ectopic overexpression of Btg2 inhibited the EMT response, blocking cell migration, and promoted cancer cell death. These data demonstrate that the combination therapy of T1-44 with Vactosertib is synergistic for pancreatic cancer, suggesting that this novel combination therapy has value in the treatment strategy of patients with pancreatic cancer.

ESRP1 is reported to regulate the alternative splicing of some genes involved in epithelial–mesenchymal transition. Here the authors show that LRRFIP2 is a target of ESRP1 and that two spliced variants of LRRFIP2 have opposing functions in gastric cancer metastasis

Suicide, a leading cause of death among the youth, has shown a positive association with high temperatures. However, few studies have explored the association between tropical nights and suicide and the potential role of greenness on this association. We investigated the association between suicide and two hot night indices: hot night duration (HNd) and hot night excess (HNe), representing heat duration and excess heat during night-time. We also explored whether the association was modified by urban greenspace, measured by satellite-derived normalized difference vegetation index (NDVI), across 25 districts in Seoul, South Korea from 2000 to 2020. Based on the multi-district daily time-series data, we performed a space-time-stratified case-crossover analysis with a distributed lag linear model with lags of up to 7 d for HNd and HNe, adjusting for daily mean temperature and relative humidity. We added an interaction term between the hot night index and NDVI to assess the effect modification of greenness. In total, 14 693 suicides were included in this study. The relative risk (RR) of suicide per a 10% increase in HNd was 1.059 (95% CI: 1.017–1.103) in low NDVI areas and 1.031 (95% CI: 0.988–1.075) in high NDVI areas. The RR per a 1 °C increase in HNe was 1.011 (95% CI: 0.998–1.024) and 1.005 (95% CI: 0.992–1.018) in low and high NDVI areas, respectively. Greenspaces have expanded over time in all districts of Seoul, and the risk of suicide for night-time heat decreased over time in both low and high NDVI areas. Our findings suggest that exposure to night-time heat is associated with an increased risk of suicide, but this risk may be mitigated by greater greenspaces in urban areas. Prioritizing development and maintenance of urban greenspaces will be a critical co-benefit strategy for promoting public mental health in changing climates.

Controlling fate decision of mesenchymal stromal cells (MSC) is important for their clinical application. Here the authors demonstrate that TGF-β-induced Mast4 suppression and Wnt-mediated Mast4 stabilization regulate MSC differentiation into cartilage and bone, respectively.

Abstract Despite favorable responses to initial chemotherapy, drug resistance is a major cause limiting chemotherapeutic efficacy in many advanced cancers. However, mechanisms that drive drug-specific resistance in chemotherapy for patients with advanced cancers are still unclear. Here, we report a unique role of death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) associated with paclitaxel resistance in cervical cancer cells. Interestingly, DRAK1 protein level was markedly decreased in paclitaxel-resistant cervical cancer cells without affecting its mRNA expression, which resulted in an increase in tumor necrosis factor receptor-associated factor 6 (TRAF6) expression, as well as an activation of TRAF6-mediated nuclear factor-kappa B (NF-κB) signaling cascade, thereby promoting tumor progression. DRAK1 depletion markedly increased the chemotherapeutic IC50 values of paclitaxel in cervical cancer cells. Ectopic expression of DRAK1 inhibited growth of paclitaxel-resistant cervical cancer cells in vitro and in vivo. Furthermore, DRAK1 was markedly underexpressed in chemoresistant cervical cancer patient tissues compared with chemosensitive samples. We found that DRAK1 protein was destabilized through K48-linked polyubiquitination promoted by the Cullin scaffold protein 3 (CUL3) / speckle-type POZ (poxvirus and zinc finger protein) protein (SPOP) E3 ubiquitin ligase in paclitaxel-resistant cells. Collectively, these findings suggest that DRAK1 may serve as a potential predictive biomarker for overcoming paclitaxel resistance in cervical cancer.

Abstract Although tetraarsenic hexoxide is known to exert an anti-tumor effect by inducing apoptosis in various cancer cells, its effect on other forms of regulated cell death remains unclear. Here, we show that tetraarsenic hexoxide induces the pyroptotic cell death through activation of mitochondrial reactive oxygen species (ROS)-mediated caspase-3/gasdermin E (GSDME) pathway, thereby suppressing tumor growth and metastasis of triple-negative breast cancer (TNBC) cells. Interestingly, tetraarsenic hexoxide-treated TNBC cells exhibited specific pyroptotic characteristics, including cell swelling, balloon-like bubbling, and LDH releases through pore formation in the plasma membrane, eventually suppressing tumor formation and lung metastasis of TNBC cells. Mechanistically, tetraarsenic hexoxide markedly enhanced the production of mitochondrial ROS by inhibiting phosphorylation of mitochondrial STAT3, subsequently inducing caspase-3-dependent cleavage of GSDME, which consequently promoted pyroptotic cell death in TNBC cells. Collectively, our findings highlight tetraarsenic hexoxide-induced pyroptosis as a new therapeutic strategy that may inhibit cancer progression of TNBC cells.

Streamlining is one of the most frequently utilized visualization methods to analyze the flow structure of computational fluid dynamics (CFD) data. However, it is challenging to find a set of streamlines showing the most prominent flow across the entire flow field due to the heavy computation time required to generate bundles of streamlines. In this paper, we propose an efficient streamline generation method that removes several seed candidates that are predicted as less important using a 3D U-net based regression model. We employ 3D line integral convolution (LIC) volumes that depict the entire flow field for training data of the proposed learning model and evaluate our method using a real-world CFD data set. We find using our model that we can obtain quality of visualization results comparable to that of the ground truth even when more than 90% of the seed candidates are truncated while operating 6.6~17.1 times faster than the competing method.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Here, the authors show that RNF208, an estrogen-induced ubiquitin ligase, promotes the degradation of Vimentin, thereby suppressing lung metastasis of TNBC, and may serve as a biomarker for the disease.

Summary: Triple-negative breast cancer (TNBC) is considered incurable with currently available treatments, highlighting the need for therapeutic targets and predictive biomarkers. Here, we report a unique role for Bcl-2-associated athanogene 2 (BAG2), which is significantly overexpressed in TNBC, in regulating the dual functions of cathepsin B as either a pro- or anti-oncogenic enzyme. Silencing BAG2 suppresses tumorigenesis and lung metastasis and induces apoptosis by increasing the intracellular mature form of cathepsin B, whereas BAG2 expression induces metastasis by blocking the auto-cleavage processing of pro-cathepsin B via interaction with the propeptide region. BAG2 regulates pro-cathepsin B/annexin II complex formation and facilitates the trafficking of pro-cathespin-B-containing TGN38-positive vesicles toward the cell periphery, leading to the secretion of pro-cathepsin B, which induces metastasis. Collectively, our results uncover BAG2 as a regulator of the oncogenic function of pro-cathepsin B and a potential diagnostic and therapeutic target that may reduce the burden of metastatic breast cancer. : The mechanisms controlling the pro- and anti-oncogenic roles of cathepsin B are unclear. Yang et al. find that BAG2 is a regulator of the dual functions of its client protein, CTSB, facilitating the progression of TNBC. Keywords: BAG2, cathepsin B, TNBC, tumorigenesis, metastasis, breast cancer, TGN38

Refugees are exposed to multiple traumatic and stressful events and thereby are at higher risk for developing a variety of psychological sequelae including posttraumatic stress disorder (PTSD). However, the relation of PTSD to other mental health conditions has not been fully revealed in refugee populations. The present study investigated relationships among trauma exposure, PTSD, depression, and insomnia in North Korean refugee youth. Seventy-four refugee youth were assessed for exposure to traumatic events, PTSD, depression, and insomnia symptoms. The results showed high rates of multiple trauma exposures among the refugee youth and high incidences of co-occurring symptoms of PTSD and insomnia in those who have multiple trauma. Furthermore, the overall symptoms and four cluster symptoms of PTSD were strongly correlated with insomnia in addition to depression. In the path model to predict insomnia, PTSD affected insomnia only through depression, indicating that the greater the levels of PTSD suffered, the greater the likelihood for developing sleep problems via depression. The present study indicates how sleep problems relate to trauma-related symptoms, i.e., PTSD and depression in refugee populations, and highlights the need for further investigation of the specific relation between sleep problems and trauma-related symptoms for effective evaluation and intervention.

Objective: To identify factors that are significantly associated with the intention to quit electronic cigarette smoking (ECS) at multiple, ecological levels among university students. Participants: 365 students who were e-cigarette users from Seoul metropolitan areas, South Korea. Methods: A cross-sectional study through an online survey. Results: Of participants, 62.7% had the intention to quit ECS--17.2% within one month, 14.0% within six months, and 31.5% when the time is right. Factors significantly associated with the intention to quit ECS were identified: "device type," "a shorter duration of ECS," and "having started ECS for quitting traditional cigarette smoking" at the intrapersonal-level; "negative attitudes of either peers or family members toward ECS" at the interpersonal-level; and "exposure to community smoking cessation educations" at the community-level. Conclusions: Approximately one-thirds of university e-cigarette users had no intention to quit ECS. The factors identified should be integrated into university level, behavioral smoking cessation strategies.

ObjectivesThis paper proposes a measurement method to quantify the abnormal characteristics of the broken parts of ribs using local texture and shape features in chest radiographs.MethodsOur measurement method comprises two steps: a measurement area assignment and sampling step using a spline curve and sampling lines orthogonal to the spline curve, and a fracture-ness measurement step with three measures, asymmetry and gray-level co-occurrence matrix based measures (contrast and homogeneity). They were designed to quantify the regional shape and texture features of ribs along the centerline. The discriminating ability of our method was evaluated through region of interest (ROI) analysis and rib fracture classification test using support vector machine.ResultsThe statistically significant difference was found between the measured values from fracture and normal ROIs; asymmetry (p < 0.0001), contrast (p < 0.001), and homogeneity (p = 0.022). The rib fracture classifier, trained with the measured values in ROI analysis, detected every rib fracture from chest radiographs used for ROI analysis, but it also classified some unbroken parts of ribs as abnormal parts (8 to 17 line sets; length of each line set, 2.998 ± 2.652 mm; length of centerlines, 131.067 ± 29.460 mm).ConclusionsOur measurement method, which includes a flexible measurement technique for the curved shape of ribs and the proposed shape and texture measures, could discriminate the suspicious regions of ribs for possible rib fractures in chest radiographs.

Category: Basic Sciences/Biologics Introduction/Purpose: Although weight-bearing CT of the foot and ankle definitely reflect the morphology of joint and foot deformity, it is hard to obtain the standing CT due to difficulty of availability. The purpose of this study is to introduce a semi- automatic method based on a deformable surface fitting for achieving the weight-bearing 3D model reconstruction from standing radiographs for foot and ankle. Methods: Our method is based on a Laplacian surface deformation framework using a template model of foot bones. As pre- processing step, we obtained template surface meshes having the average shapes of foot bones from standing CT images (Planmed Verity® CT scanner) in 10 normal volunteers. First, 3D standing CT was obtained by Planmed Verity® CT scanner and used as gold standard of reconstruction for one patient with flatfoot. Second, in the reconstruction step, the surface meshes are deformed following guided user inputs (talus 6, calcaneus 8 in lateral, talus 6, calcaneus 6 in anteroposterior standing radiograph) with geometric constraints to recover the target shapes of patients while preserving average bone shape and smoothness as much as possible. Finally, we compared reconstructed 3D model to original standing CT images. Results: In this study, the comparison results indicate that the obtained reconstruction is close to the actual standing foot and ankle geometry. We present the accuracy and robustness of our method via comparison between the reconstructed 3D models and the original bone surfaces Conclusion: Weight-bearing 3D foot model reconstruction from standing radiographs is concise and the effective method for analysis of foot joint alignment and deformity.

Mammalian cells have a well-defined set of antioxidant enzymes, which includes superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins. Peroxiredoxins are the most recently identified family of antioxidant enzymes that catalyze the reduction reaction of peroxides, such as H2O2. In particular, typical 2-Cys peroxiredoxins are the featured peroxidase enzymes that receive the electrons from NADPH by coupling with thioredoxin and thioredoxin reductase. These enzymes distribute throughout the cellular compartments and, therefore, are thought to be broad-range antioxidant defenders. However, recent evidence demonstrates that typical 2-Cys peroxiredoxins play key signal regulatory roles in the various signaling networks by interacting with or residing near a specific redox-sensitive molecule. These discoveries help reveal the redox signaling landscape in mammalian cells and may further provide a new paradigm of therapeutic approaches based on redox signaling.

BACKGROUND: Deep sequencing techniques provide a remarkable opportunity for comprehensive understanding of tumorigenesis at the molecular level. As omics studies become popular, integrative approaches need to be developed to move from a simple cataloguing of mutations and changes in gene expression to dissecting the molecular nature of carcinogenesis at the systemic level and understanding the complex networks that lead to cancer development. RESULTS: Here, we describe a high-throughput, multi-dimensional sequencing study of primary lung adenocarcinoma tumors and adjacent normal tissues of six Korean female never-smoker patients. Our data encompass results from exome-seq, RNA-seq, small RNA-seq, and MeDIP-seq. We identified and validated novel genetic aberrations, including 47 somatic mutations and 19 fusion transcripts. One of the fusions involves the c-RET gene, which was recently reported to form fusion genes that may function as drivers of carcinogenesis in lung cancer patients. We also characterized gene expression profiles, which we integrated with genomic aberrations and gene regulations into functional networks. The most prominent gene network module that emerged indicates that disturbances in G2/M transition and mitotic progression are causally linked to tumorigenesis in these patients. Also, results from the analysis strongly suggest that several novel microRNA-target interactions represent key regulatory elements of the gene network. CONCLUSIONS: Our study not only provides an overview of the alterations occurring in lung adenocarcinoma at multiple levels from genome to transcriptome and epigenome, but also offers a model for integrative genomics analysis and proposes potential target pathways for the control of lung adenocarcinoma.

The p53 and NF-κB pathways play important roles in diverse cellular functions, including cell growth, apoptosis, and tumorigenesis. Mutations that inactivate the p53 gene and constitutive NF-κB pathway activation are common occurrences in human cancers. Although many drugs are being developed that selectively activate p53 or inhibit NF-κB, there are few drug candidates that can do both. Simultaneous activation of p53 and inhibition of the NF-κB pathway is therefore a prime target for new cancer drug development. This study is the first report of a high-throughput approach with mass compounds that concurrently target both pathways. Using a cell-based screening assay and a library of 200,000 synthetic compounds, we identified 9 small molecules that simultaneously inhibit NF-κB and activate p53. One of these compounds, N-2, increased the expression of p53 target genes, including p21 and GADD45a. In addition, N-2 inhibited the transcriptional activity of NF-κB, concomitantly repressing interleukin-6 and monocyte chemotactic protein-1 (MCP-1) expression. When cell lines derived from a diverse range of cancers were treated in vitro with N-2, we observed increased cell death. N-2 also significantly inhibited allograft growth in murine models of melanoma and lung carcinoma. Our findings suggest that N-2 may act as a bivalent anti-cancer agent through simultaneous modulation of NF-κB and p53 activities.

Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer.In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity.The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been shown to exert a synergistic antitumor effect when combined with fluoropyrimidine. This synergy may be attributable to the downregulation of thymidylate synthase (TS), which is frequently overexpressed in fluoropyrimidine-resistant cancer cells. However, the molecular mechanism underlying the downregulation of TS has yet to be clearly elucidated. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we demonstrate that lapatinib, a dual TKI of EGFR and HER2 downregulates TS via inhibition of the nuclear translocation of EGFR and HER2. From our cDNA microarray experiments, we determined that a variety of nucleotide synthesis-related genes, including TS, were downregulated with lapatinib, and this was apparent in HER2-amplified cells. Targeted and pharmacologic inhibition assays confirmed that the dual inhibition of EGFR and HER2 is required for the more effective reduction of TS as compared to what was observed with gefitinib or trasutuzumab alone. Additionally, we determined that co-transfected EGFR and HER2 activate the TS gene promoter more profoundly than do either EGFR or HER2 alone. The translocation of EGFR and HER2 into the nucleus and the subsequent activation of the TS promoter were inhibited by lapatinib. CONCLUSIONS AND SIGNIFICANCE: These results demonstrate that lapatinib inhibits the nuclear translocation of EGFR and HER2 and downregulates TS, thus sensitizing cancer cells to fluoropyrimidine.