Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.

Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.

Experimental Verification of the Impact of the Contact Area between the Defect Site and the Scaffold on Bone Regeneration Efficacy.

In the field of bone tissue engineering, which is being developed for the ideal restoration of bone defects, researchers are exploring the improvement of the bone regeneration efficacy of scaffolds through various approaches involving osteoconductive, osteoinductive, and angiogenic factors. In the current trend of research, there is also a suggestion that the topological factors of recent scaffolds may influence the attachment, migration, proliferation, and differentiation of bone cells. Building upon experimental confirmation of the effect of scaffold conformity with the defect site on enhanced bone regeneration in previous studies, we conducted this research to experimentally investigate the relationship between contact area with the defect site and bone regeneration efficacy. The results demonstrated that as the contact area of the scaffold increased, not only did the resistance to bone tissue growth increase, more significant bone regeneration also occurred, as evidenced through histological analysis and micro-CT analysis. This research confirms that the contact area between the scaffold and the defect site is a critical variable affecting bone regeneration efficacy, emphasizing its importance when designing customized scaffolds. This finding holds promising implications for future studies and applications in the field.

Expansion of CD45RA-FOXP3++ regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation.

OBJECTIVES: Simultaneous transplantation of a solid organ and bone marrow from the same donor is a possible means of achieving transplant tolerance. Here, we attempted to identify biomarkers that indicate transplant tolerance for discontinuation of immunosuppressants in combined kidney and bone marrow transplantation (CKBMT). METHODS: Conventional kidney transplant (KT) recipients (n = 20) and CKBMT recipients (n = 6) were included in this study. We examined various immunological parameters by flow cytometry using peripheral blood mononuclear cells (PBMCs), including the frequency and phenotype of regulatory T (Treg) cell subpopulations. We also examined the suppressive activity of the Treg cell population in the setting of mixed lymphocyte reaction (MLR) with or without Treg cell depletion. RESULTS: Among six CKBMT recipients, three successfully discontinued immunosuppressants (tolerant group) and three could not (non-tolerant group). The CD45RA-FOXP3++ Treg cell subpopulation was expanded in CKBMT recipients compared to conventional kidney transplant patients, and this was more obvious in the tolerant group than the non-tolerant group. In addition, high suppressive activity of the Treg cell population was observed in the tolerant group. The ratio of CD45RA-FOXP3++ Treg cells to CD45RA-FOXP3+ cells indicated good discrimination between the tolerant and non-tolerant groups. CONCLUSION: Thus, our findings propose a biomarker that can distinguish CKBMT patients who achieve transplant tolerance and are eligible for discontinuation of immunosuppressants and may provide insight into tolerance mechanisms in CKBMT.

Shikonin inhibits proliferation of melanoma cells by MAPK pathway-mediated induction of apoptosis.

Shikonin, a natural product isolated from the roots of Lithospermum erythrorhizon, exhibits pharmacological effects against inflammation, ulcers, infections, and tumors. In the present study, we aimed to investigate the antitumor effects of shikonin on the human melanoma cell line, A375SM, and in an in vivo mouse xenograft model. We examined the anticancer effects of shikonin by in vitro experiments (MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, 4',6-diamidino-2-phenylindole (DAPI) stain, annexin V/ propidium iodide (PI) stain, and protein analysis of apoptosis and mitogen-activated protein kinase (MAPK) pathways). Further, the anticancer effect in vivo was confirmed through a xenograft model. Our results showed that shikonin inhibited the proliferation of melanoma cells in a dose-dependent manner. In addition, shikonin significantly increased nucleus and chromatin condensation and early/late apoptosis. Shikonin also increased the pro-apoptotic proteins and decreased the anti-apoptotic proteins. Additionally, shikonin was overexpressed in MAPK pathways. Investigation of the effects of shikonin in a mouse xenograft model not only showed decreased A375SM tumor volume but also increased apoptosis as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Furthermore, pathologic changes were not observed in the liver and kidney of mice. Collectively, the study indicated that shikonin inhibited the proliferation of the human melanoma cells by inducing apoptosis, mediated by MAPK pathway and that it is a potential candidate for an anticancer drug against melanoma cancer.

Late complication of the Nuss procedure: recurrent cardiac tamponade.

Pectus excavatum (PE) is known as one of the most common congenital deformities of the anterior chest wall. The Nuss procedure is an effective surgical therapy to correct PE. Here, we report a case of recurrent cardiac tamponade due to hemopericardium that occurred after 16 months following the Nuss procedure. The cause of recurrent hemopericardium was thought to be local, repetitive irritation of the pericardium by the Nuss steel bar. We should keep in mind that this serious complication can occur after the Nuss procedure, even in the late phase.

A case of vitamin D hydroxylation-deficient rickets type 1A caused by 2 novel pathogenic variants in CYP27B1 gene.

Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A, OMIM 264700) is a rare autosomal recessive inherited disorder. Pathogenic variants in the CYP27B1 gene lead to loss of 1α-hydroxylase activity. We report the case of a 22-month-old toddler who presented with growth retardation and delayed development. The patient exhibited the typical laboratory findings of VDDR1A, including hypocalcemia (calcium: 5.2 mg/dL), elevated serum level of alkaline phosphatase (2,600 U/L), elevated serum level of intact-parathyroid hormone (238 pg/mL), low 1,25(OH)2D3 level (11.2 pg/mL), and normal 25(OH)D3 level (40.7 ng/mL). His height and weight were 76.5 cm and 9.5 kg, respectively (both <3rd percentile). The Bayley Scales of Infant and Toddler Development II indicated significantly delayed development (mental development index <50, psychomotor development index <50). The patient was a compound heterozygous for two novel pathogenic variants in the CYP27B1 gene: c.57_69del (p.Glu20Profs*2) and c.171dupG (p.Leu58Alafs*275), inherited from his mother and father, respectively. The patient showed remarkable improvement after treatment with calcitriol and calcium carbonate.

Fluorinated Bioactive Glass Nanoparticles: Enamel Demineralization Prevention and Antibacterial Effect of Orthodontic Bonding Resin.

Orthodontic treatment involving the bonding of fixed appliances to tooth surfaces can cause white spot lesions (WSLs). WSLs increase the likelihood of cavity formation and hence require preservation and prosthetic restoration. Therefore, the prevention of WSLs is of greater importance than treatment. Application of fluoride or the use of fluoride-containing mouthwash can prevent WSLs, but this requires patient cooperation and additional time and cost. Bioactive glass containing 2.5% fluoride was synthesized and mixed with the orthodontic bonding adhesive Transbond XT Low Flow (LV) at ratios of 1, 3, and 5% to prepare orthodontic adhesive samples. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) were used to characterize the samples. The Vickers hardness test, bracket retention test, and adhesive remnant index (ARI) of the samples were analysed to determine their mechanical properties. To determine the biological cytotoxicity, the cell activity of the samples was evaluated using cell viability tests and the antibacterial activity was analysed using Streptococcus mutans. To evaluate the anti-demineralization effect, the sample was bonded to extracted teeth and a pH cycle test was performed. Micro computed tomography data were obtained from the bonded teeth and sample, and the anti-demineralization effect was evaluated using the ImageJ software program. The Vickers hardness of the sample was higher than that of LV and was dependent on the concentration of fluoride-containing bioactive glass (FBAG). The bracket retention test and ARI of the sample showed no significant differences from those of LV. The cell viability test showed no significant changes at 24 and 48 h after application of the sample. The fluoride ion release test indicated an ion release rate of 9.5-17.4 µg/cm2. The antibacterial activity of the experimental group containing FBAG was significantly higher than that of the LV group. The anti-demineralization test showed a concentration-dependent increase. However, the resin containing 5 mass% FBAG (FBAG5) showed a statistically-significant increase compared with LV. The orthodontic adhesive containing FBAG showed antibacterial and anti-demineralization effects, thus indicating possible WSL prevention activity.

Enamel Surface Remineralization Effect by Fluorinated Graphite and Bioactive Glass-Containing Orthodontic Bonding Resin.

All orthodontic appliances are potentially cariogenic. The plaque around the orthodontic appliance can make demineralization on tooth surface causing white spot lesion (WSL). The most effective method to prevent WSL is Fluoride appliance and gargling, but this requires patient cooperation, which consumes additional treatment time and cost. As suggested in this study, biomaterials like bioactive glass and fluorinated graphite (FGt) having antibacterial and anti-demineralization ability effective and easy to use in the clinic. To clinically use orthodontic bonding resins containing Graphite Fluoride BAG (FGtBAG), its properties, biological stability, antimicrobial activity, and remineralization effect must be verified. BAG was mixed with 2.5% FGt containing 51 to 61% fluorine. This mixture was mixed with the CharmFill Flow (CF) in the ratios of 1, 3, and 5 wt%. Microhardness and shear bond strength tests were performed to evaluate its mechanical properties. MTT (3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetra) assay was performed for evaluating its safety. Streptococcus mutans, which is major cariogen by producing lactic acid, was evaluated for antibacterial ability of reducing WSL. In addition, x-ray images were obtained by CBCT (Cone beam computed tomography) after a pH cycle. The remineralization effect was verified in vivo and by Image J. FGtBAG did not differ significantly from CF in mechanical tests. The MTT assay found no significant differences between the groups. The antibacterial activity of FGtBAG at 24 h and 48 h was significantly higher than that of CF. The fluoride release rate tended to increase with the FGtBAG content. The pH cycle results showed that FGtBAG had higher concentration-dependent remineralization effect than CF. The results of this study suggests that orthodontic resins containing FGtBAG can prevent WSL owing to their antibacterial activity and remineralization effect.

Antibacterial and remineralization effects of orthodontic bonding agents containing bioactive glass.

OBJECTIVE: The aim of this study was to evaluate the mechanical and biological properties of orthodontic bonding agents containing silver- or zinc-doped bioactive glass (BAG) and determine the antibacterial and remineralization effects of these agents. METHODS: BAG was synthesized using the alkali-mediated solgel method. Orthodontic bonding agents containing BAG were prepared by mixing BAG with flowable resin. Transbond™ XT (TXT) and Charmfil™ Flow (CF) were used as controls. Ion release, cytotoxicity, antibacterial properties, the shear bond strength, and the adhesive remnant index were evaluated. To assess the remineralization properties of BAG, micro-computed tomography was performed after pH cycling. RESULTS: The BAG-containing bonding agents showed no noticeable cytotoxicity and suppressed bacterial growth. When these bonding agents were used, demineralization after pH cycling began approximately 200 to 300 µm away from the bracket. On the other hand, when CF and TXT were used, all surfaces that were not covered by the adhesive were demineralized after pH cycling. CONCLUSIONS: Our findings suggest that orthodontic bonding agents containing silver- or zinc-doped BAG have stronger antibacterial and remineralization effects compared with conventional orthodontic adhesives; thus, they are suitable for use in orthodontic practice.

Therapeutic strategies for locally recurrent and metastatic de-differentiated liposarcoma with herpes simplex virus-thymidine kinase-expressing mesenchymal stromal cells.

BACKGROUND AIMS: Major challenges in de-differentiated liposarcoma (DDLPS) therapy are the high rate of sequential recurrence (>80%) and metastasis (20-30%) following surgical removal. However, well-defined therapeutic strategies for this rare malignancy are lacking and are critically needed. METHODS: We investigated a new approach to DDLPS therapy with mesenchymal stromal cells expressing herpes simplex virus-thymidine kinase (MSC-TK). In an effort to evaluate this efficacy, in vitro cytotoxicity of MSC-TK against DDLPS cells was analyzed using an apoptosis assay. For pre-clinical study, the MSC-TK-induced reduction in recurrence and metastasis was validated in a recurrent DDLPS model after the macroscopic complete resection and lung metastasis DDLPS model. RESULTS: MSC-TK induced apoptosis in DDLPS cells by bystander effects via gap junction intracellular communication (GJIC) of toxic ganciclovir (GCV). Recurrent DDLPS models following no residual tumor/microscopic tumor resection and lung metastasis DDLPS models were established, which suggested clinical relevance. MSC-TK markedly reduced locoregional recurrence rates and prolonged recurrence-free survival, thus increasing overall survival in the recurrent DDLPS model. MSC-TK followed by GCV treatment yielded a statistically significant reduction in early- and advanced-stage lung metastasis. DISCUSSION: This therapeutic strategy may serve as an alternative or additional strategy by applying MSC-TK to target residual tumors following surgical resection, thus reducing local relapse and metastasis in these patients.

How far is the root apex of a unilateral impacted canine from the root apices' arch form?

INTRODUCTION: The purpose of this study was to determine the arch form of the root apices of normally erupting teeth and then determine the differences in the location of the apex of impacted canines relative to normally erupting canines. In addition, we sought to determine whether the labiopalatal position of the impacted canines influences the position of the apices. METHODS: The study included 21 patients with unerupted canines that subsequently had a normal eruption, 21 patients with palatally impacted canines, 27 patients with labially impacted canines, and 17 patients with midalveolus impacted canines. Images were obtained using cone beam computed tomography, and the x, y, and z coordinates of the root apices were determined using Ondemand3D software (Cybermed Co., Seoul, Korea). Two-dimensional coordinates were converted from acquired 3-dimensional coordinates via projection on a palatal plane, and the Procrustes method was used to process the converted 2-dimensional coordinates and to draw the arch forms of the root apices. Finally, we measured the extent of root apex deviation from the arch forms of the root apices. RESULTS: Normally erupting canines showed that even though calcifications may be immature, their positions were aligned with a normal arch form. The root apices of the impacted canines were an average of 6.572 mm away from the root apices' arch form, whereas those of the contralateral nonimpacted canines were an average distance of 2.221 mm away, a statistically significant difference. The palatally impacted canines' root apices distribution tended toward the first premolar root apices. CONCLUSIONS: Incompletely calcified, unerupted teeth with a subsequent normal eruption showed a normal arch form of the root apices. The root apices of impacted canines were farther from the arch forms than were the nonimpacted canines. Also, the root apices of impacted canines in the palatal area showed distributions different from those of the other impacted canine groups.

Statistical shape analysis-based determination of optimal midsagittal reference plane for evaluation of facial asymmetry.

INTRODUCTION: The purpose of this study was to determine, by statistical shape analysis of original and mirrored skeletal landmarks, the optimal landmark-based midsagittal reference plane for evaluation of facial asymmetry. METHODS: The study sample comprised 69 patients with facial asymmetry (36 men, 33 women; mean age, 23.0 ± 4.1 years). All landmarks were obtained with cone-beam computed tomography using a 3-dimensional coordinate system. For identifying the landmark-based midsagittal reference plane, the 3 landmarks nearest to the symmetric midsagittal reference plane were selected by ordinary and generalized Procrustes analyses. To verify the 3-landmark-based midsagittal reference plane's compatibility with the symmetric midsagittal reference plane, asymmetry measurements were calculated and tested for each. RESULTS: The 3 nearest landmarks (nasion, anterior nasal spine, and posterior nasal spine) were selected for the 3-landmark-based midsagittal reference plane. The averages of the sums of the squared Euclidean distance and the squared Procrustes distance differences between the 2 configurations and shapes fabricated by the symmetric and landmark-based midsagittal reference planes, respectively, were calculated as 0.121 ± 0.241 mm and 1.69 × 10(-6) ± 3.25 × 10(-6). The testing results for the symmetric and landmark-based midsagittal reference planes were almost the same. CONCLUSION: The results indicated that a 3-dimensional midsagittal reference plane constructed of nasion, anterior nasal spine, and posterior nasal spine could be a valuable tool for the evaluation of patients with facial asymmetry.

Association between restriction of activity related to chronic diseases and suicidal ideation in older adults in Korea.

AIM: The aim of the present study was to show an association between restricted activity related to chronic diseases and suicidal ideation (SI) in elderly Korean adults after adjusting for age, sex, mental health status, socioeconomic position and health behavior factors. METHODS: The study sample included 3545 Korean men (n=1473) and women (n=2073), aged over 65 years from the 2007-2009 Korea National Health and Nutrition Examination Survey carried out by the Ministry of Health and Welfare of Korea. Participants were classified into two groups based on whether they had previously experienced suicidal thoughts. Restricted activity was related to chronic conditions, such as cardiovascular diseases, cerebrovascular accident and so on. We analyzed the data using Student's t-test or χ(2) -test. Multiple logistic regression analysis was used to determine the association between restricted activity as the independent variable and SI as the dependent variable after adjustment for confounders. RESULTS: The proportion of participants with SI population was 29.1%. People with SI reported a significantly higher proportion of restrictive activity (62.3%) than those who did not have SI (34.5%). The adjusted risk excess (OR) of SI was statistically significant with regard to restricted activity (2.11, 95% CI 1.65-2.70; 2.85, 95% CI 1.95-4.15) in males; 1.69 (95% CI 1.22-2.34) in females after adjustment for potential confounders. In particular, women who lived alone showed high adjusted OR (1.50, 95% CI 1.01-2.24). CONCLUSIONS: Statistical analyses from this community-based, random sample drawn from a selected sample of the elderly Korean population showed that restricted activity appears to be significantly associated with SI.

Establishment of primary xenograft model from newly characterized patient extrauterine carcinosarcoma.

BACKGROUND AND OBJECTIVE: The aim of this study was to characterize primary cells from extrauterine carcinosarcoma (CS) and to establish a primary CS xenograft mouse model. METHODS: Primary cells were isolated from a patient with CS and cultured in vitro. Primary CS cells were verified for their ability to consecutively generate tumorigenesis in NOD/SCID mice. The properties of xenograft tumor and explants cells were investigated by immunohistochemistry, cytogenetic, and FACS analysis. Anticancer drug susceptibility of primary CS was analyzed using CCK-8. RESULTS: Primary CS cells greater than 27 passages in vitro showed an ability of a series of xenograft tumorigenesis in vivo having the same marker expression and cytogenetic character as that of original tumor. In addition, explants of xenograft tumors retained their original characteristics in the in vitro culture system. Finally, the analysis of the susceptibility to anticancer drug revealed that primary CS cells were susceptible to both doxorubicin and nilotinib, which are tyrosine kinase inhibitors. CONCLUSIONS: The primary CS cells and the primary CS xenograft tumorigenesis introduce a new therapeutic model for targeting cancer and also explore a deeper understanding of generation of the tumor itself.

Expression and functional significance of the erythropoietin receptor in hepatocellular carcinoma.

BACKGROUND: Erythropoietin, through its specific receptor (EpoR), may induce responses in a variety of non-haematopoietic tissues including malignant cells. The purpose of this study was to examine the expression of EpoR in hepatocellular carcinoma (HCC) and to correlate the levels of EpoR expression with the clinicopathological properties of HCC and tumour recurrence. METHODS: The study included 134 patients who underwent curative hepatectomy for hepatitis B virus (HBV)-related primary HCC. The clinical, laboratory and pathological data from these patients were retrospectively collected. The expression of EpoR mRNA and protein were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. RESULTS: Expression of EpoR mRNA in the cirrhotic liver was positively correlated with tumour cell differentiation and 1-year disease-free survival (74.8% in the high expression group versus 46.9% in the low expression group; P = 0.001), as it was for EpoR mRNA expression in HCC (64.4% in the high expression group versus 52.7% in the low expression group; P = 0.044). Tumour recurrence showed stronger dependence on the expression of EpoR protein in non-malignant cirrhotic livers than in HCC. CONCLUSION: In HBV-related HCC, the levels of EpoR mRNA and protein in non-tumour cirrhotic livers were positively correlated with tumour cell differentiation, which is a favourable predictor of disease-specific survival.

Outcomes according to presentation with versus without cardiogenic shock in patients with left main coronary artery stenosis and acute myocardial infarction.

This study is aimed at evaluating 1-year clinical outcomes and their predictors in patients with unprotected left main coronary artery (ULMCA)-related acute myocardial infarction (AMI). In total 248 patients diagnosed with AMI involving the ULMCA as the culprit vessel and registered in the Korean Acute Myocardial Infarction database were enrolled in this study. Patients were divided according to the absence (shock-, n = 206) or presence (shock+, n = 42) of cardiogenic shock at initial presentation. Independent risk factors of in-hospital cardiac death associated with ULMCA-related AMI were elucidated by multivariate regression analysis. In-hospital mortality rates were 8.7% in the shock- group and 47.6% in the shock+ group (p = 0.001). During 1-year follow-up after discharge, major adverse cardiac events developed in 16.3% of patients in the shock- group and 18.2% of patients in the shock+ group (p = 0.828); cardiac death, MI, and ischemia-driven target vessel revascularization were similar between the 2 groups at 1 year. On multivariate analysis, initial shock presentation (odds ratio 8.9, confidence interval 4.1 to 19.2, p = 0.004) and left ventricular ejection fraction <30% (odds ratio 7.6, confidence interval 2.7 to 21.1, p = 0.001) were independent risk factors of in-hospital cardiac death associated with ULMCA-related AMI. In conclusion, almost 1/2 of patients with ULMCA-related AMI presenting with cardiogenic shock had a fatal in-hospital outcome compared to <10% of those without cardiogenic shock; however, clinical outcomes after survival of the in-hospital period were not different between these groups.