Differential diagnosis of cemento-osseous dysplasia and periapical cyst using texture analysis of CBCT.

BACKGROUND: Radiolucencies found at the root apex in patients with cemento-osseous dysplasia (COD) may be mistaken for periapical cysts (PC) of endodontic origin. The purpose of this study was to examine the utility of quantitative texture analysis using cone-beam computed tomography (CBCT) to differentiate between COD and PC. METHODS: Patients who underwent CBCT at Wonkwang University Daejeon Dental Hospital between January 2019 and December 2022 and were diagnosed with COD and PC by clinical, radiologic, and, if necessary, histopathologic examination were included. Twenty-five patients each were retrospectively enrolled in the COD and PC group. All lesions observed on axial CBCT images were manually segmented using the open-access software MaZda version 4.6 to establish the regions of interest, which were then subjected to texture analysis. Among the 279 texture features obtained, 10 texture features with the highest Fisher coefficients were selected. Statistical analysis was performed using the Mann-Whitney U-test, Welch's t-test, or Student's t-test. Texture features that showed significant differences were subjected to receiver operating characteristics (ROC) curve analysis to evaluate the differential diagnostic ability of COD and PC. RESULTS: The COD group consisted of 22 men and 3 women, while the PC group consisted of 14 men and 11 women, showing a significant difference between the two groups in terms of sex (p=0.003). The 10 selected texture features belonged to the gray level co-occurrence matrix and included the sum of average, sum of entropy, entropy, and difference of entropy. All 10 selected texture features showed statistically significant differences (p<0.05) when comparing patients with COD (n=25) versus those with PC (n=25), osteolytic-stage COD (n=11) versus PC (n=25), and osteolytic-stage COD (n=11) versus cementoblastic-stage COD (n=14). ROC curve analysis to determine the ability to differentiate between COD and PC showed a high area under the curve ranging from 0.96 to 0.98. CONCLUSION: Texture analysis of CBCT images has shown good diagnostic value in the differential diagnosis of COD and PC, which can help prevent unnecessary endodontic treatment, invasive biopsy, or surgical intervention associated with increased risk of infection.

Resorptive Root Features in Mandibular Molars with Pronounced Root Divergence on Panoramic Radiographs: A Case Series.

INTRODUCTION: The visualization and understanding of the details of the root configurations and root canal structure are essential prior to root canal treatment. This study aimed to identify key indicators of pronounced root divergence between the distobuccal and distolingual roots in mandibular first molars by highlighting common features observed in panoramic radiographs. These indicators can help predict the likelihood of encountering significant root divergence before initiating endodontic treatment. CASE PRESENTATION: We present three cases in which panoramic radiographs displayed imaging features characteristic of root resorption in the distal root of the mandibular first molars. However, subsequent periapical radiographs in case 1 and cone-beam computed tomography images in cases 2 and 3 revealed that the mandibular first molars were in normal condition, with pronounced root divergence but no evidence of root resorption. CONCLUSION: Panoramic radiographs depicting mandibular molar roots with a resorptive and unclear appearance may indicate the presence of severe root divergence. In such cases, we strongly recommend additional cone-beam computed tomographic imaging to ensure precise diagnosis and facilitate optimal treatment planning for endodontic procedures.

Findings of Angiography and Carotid Vessel Wall Imaging Associated with Post-Procedural Clinical Events after Carotid Artery Stenting.

PURPOSE: Vessel wall imaging (VWI) for carotid plaque is better for detecting unstable carotid plaque such as intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), and thin/ruptured fibrous cap. However, the role of VWI before carotid artery stenting (CAS) is unclear. Thus, this study aimed to determine the findings of symptomatic carotid stenosis before CAS on angiography and carotid VWI and to evaluate the imaging findings associated with post-procedural clinical events after CAS. MATERIALS AND METHODS: This retrospective study included 173 consecutive patients who underwent carotid VWI, CAS, and post-procedural diffusion-weighted imaging (DWI) after CAS. Findings of unstable plaque on carotid VWI and unstable findings on angiography were analyzed. We also analyzed the incidence of post-procedural clinical events, any stroke, myocardial infarction (MI), and death within 30 days of CAS. RESULTS: Of 173 patients, 101 (58.4%) had initial ischemic symptoms and positive findings on DWI. Symptomatic patients were significantly higher in patients with IPH than in patients without IPH (62.4% vs. 45.8%, P=0.031). Degree of stenosis, thrombus of the stenotic lesion, flow delay of internal carotid artery, and flow arrest by filter thrombus had significantly higher prevalence in the symptomatic group. Twenty patients (11.6%) had post-procedural clinical events such as any stroke, clinical symptoms, and/or MI. Hyperlipidemia and intraluminal thrombus on angiography were identified as significant factors influencing post-procedural events after CAS. CONCLUSION: An intraluminal thrombus on angiography was identified as a significant factor influencing post-procedural clinical events after CAS.

TREX1 Deficiency Induces ER Stress-Mediated Neuronal Cell Death by Disrupting Ca2+ Homeostasis.

TREX1 is an exonuclease that degrades extranuclear DNA species in mammalian cells. Herein, we show a novel mechanism by which TREX1 interacts with the BiP/GRP78 and TREX1 deficiency triggers ER stress through the accumulation of single-stranded DNA and activates unfolded protein response (UPR) signaling via the disruption of the TREX1-BiP/GRP78 interaction. In TREX1 knockdown cells, the activation of ER stress signaling disrupted ER Ca2+ homeostasis via the ERO1α-IP3R1-CaMKII pathway, leading to neuronal cell death. Moreover, TREX1 knockdown dysregulated the Golgi-microtubule network through Golgi fragmentation and decreased Ac-α-tubulin levels, contributing to neuronal injury. These alterations were also observed in neuronal cells harboring a TREX1 mutation (V91M) that has been identified in hereditary spastic paraplegia (HSP) patients in Korea. Notably, this mutation leads to defects in the TREX1-BiP/GRP78 interaction and mislocalization of TREX1 from the ER and possible disruption of the Golgi-microtubule network. In summary, the current study reveals TREX1 as a novel regulator of the BiP/GRP78 interaction and shows that TREX1 deficiency promotes ER stress-mediated neuronal cell death, which indicates that TREX1 may hold promise as a therapeutic target for neurodegenerative diseases such as HSP.

Comparison of the canal transportation of ProTaper GOLD, WaveOne GOLD, and TruNatomy in simulated double-curved canals.

BACKGROUND: In root canal preparations, it is important to maintain the original canal shape. However, it is difficult to accomplish this, especially due to the complex canal anatomy. This study aimed to compare the shaping ability of the ProTaper GOLD, WaveOne GOLD, and newly developed TruNatomy in simulated S-shaped canals. METHODS: The root canals of 60 S-shaped resin blocks were dyed using ink and photographed. The blocks were then randomly divided into three groups: group ProTaper GOLD (n = 20), WaveOne GOLD (n = 20), and TruNatomy (n = 20). The simulated canals were instrumented according to the NiTi file system and photographed again after being dyed with red ink. The pre- and post-preparation images were superimposed, and the amount of resin removed from both the mesial and distal sides of the canal measured up to 9 mm from the apical terminus, with a 1 mm increment. The preparation time was also calculated. A paired t-test was used to determine the degree of deviation at different levels within the groups. To compare the degree of transportation at different levels between the groups, one-way ANOVA and Kruskal-Wallis tests were performed according to the normality. RESULTS: TruNatomy showed a significant deviation between the mesial and distal sides of the canal only in the coronal area at 6, 7, 8, and 9 mm levels of the canal (p < 0.05). When comparing the amount of transportation in the 3 groups at 9 different levels, TruNatomy showed significantly less canal transportation than the other groups at the 3-and 5-mm levels of the canal (p < 0.05), while ProTaper GOLD showed the largest amount of transportation in the apical curved area at the 2 and 3 mm levels (p < 0.05). TruNatomy removed less resin than other groups in all sections (p < 0.05), while ProTaper GOLD removed slightly more resin than WaveOne GOLD; however, there was no significant difference (p = 0.043). Shaping time was the least for TruNatomy, followed by the WaveOne GOLD and ProTaper GOLD (p < 0.05). CONCLUSIONS: TruNatomy maintained the original apical canal curvature in S-shaped curved canals better than ProTaper GOLD and WaveOne GOLD.

The emerging genetic diversity of hereditary spastic paraplegia in Korean patients.

Hereditary Spastic Paraplegias (HSP) are a group of rare inherited neurological disorders characterized by progressive loss of corticospinal motor-tract function. Numerous patients with HSP remain undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel genetic variations related to HSP is needed. In this study, we identified 88 genetic variants in 54 genes from whole-exome data of 82 clinically well-defined Korean HSP families. Fifty-six percent were known HSP genes, and 44% were composed of putative candidate HSP genes involved in the HSPome and originally reported neuron-related genes, not previously diagnosed in HSP patients. Their inheritance modes were 39, de novo; 33, autosomal dominant; and 10, autosomal recessive. Notably, ALDH18A1 showed the second highest frequency. Fourteen known HSP genes were firstly reported in Koreans, with some of their variants being predictive of HSP-causing protein malfunction. SPAST and REEP1 mutants with unknown function induced neurite abnormality. Further, 54 HSP-related genes were closely linked to the HSP progression-related network. Additionally, the genetic spectrum and variation of known HSP genes differed across ethnic groups. These results expand the genetic spectrum for HSP and may contribute to the accurate diagnosis and treatment for rare HSP.

The Human TOR Signaling Regulator Is the Key Indicator of Liver Cancer Patients' Overall Survival: TIPRL/LC3/CD133/CD44 as Potential Biomarkers for Early Liver Cancers.

Recently, we reported the involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness. This study assessed the human TOR signaling regulator (TIPRL)/microtubule-associated light chain 3 (LC3)/prominin-1 (CD133)/cluster of differentiation 44 (CD44) as potential diagnostic and prognostic biomarkers for early liver cancer. For the assessment, we stained tissues of human liver disease/cancer with antibodies against TIPRL/LC3/CD133/CD44/CD46, followed by confocal observation. The roles of TIPRL/LC3/CD133/CD44/CD46 in liver normal and cancer cell lines were determined by in vitro studies. We analyzed the prognostic and diagnostic potentials of TIPRL/LC3/CD133/CD44/CD46 using the receiver-operating characteristic curve, a Kaplan-Meier and uni-/multi-Cox analyses. TIPRL and LC3 were upregulated in tissues of HCCs and adult hepatocytes-derived liver diseases while downregulated in iCCA. Intriguingly, TIPRL levels were found to be critically associated with liver cancer patients' survivability, and TIPRL is the key player in liver cancer cell proliferation and viability via stemness and self-renewal induction. Furthermore, we demonstrate that TIPRL/LC3/CD133 have shown prominent efficiency for diagnosing patients with grade 1 iCCA. TIPRL/LC3/CD133/CD44 have also provided excellent potential for prognosticating patients with grade 1 iCCA and grade 1 HCCs, together with demonstrating that TIPRL/LC3/CD133/CD44 are, either individually or in conjunction, potential biomarkers for early liver cancer.

Corrigendum: Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families.

[This corrects the article DOI: 10.3389/fgene.2020.590924.].

Deep-learning for predicting C-shaped canals in mandibular second molars on panoramic radiographs.

OBJECTIVE: The aim of this study was to evaluate the use of a convolutional neural network (CNN) system for predicting C-shaped canals in mandibular second molars on panoramic radiographs. METHODS: Panoramic and cone beam CT (CBCT) images obtained from June 2018 to May 2020 were screened and 1020 patients were selected. Our dataset of 2040 sound mandibular second molars comprised 887 C-shaped canals and 1153 non-C-shaped canals. To confirm the presence of a C-shaped canal, CBCT images were analyzed by a radiologist and set as the gold standard. A CNN-based deep-learning model for predicting C-shaped canals was built using Xception. The training and test sets were set to 80 to 20%, respectively. Diagnostic performance was evaluated using accuracy, sensitivity, specificity, and precision. Receiver-operating characteristics (ROC) curves were drawn, and the area under the curve (AUC) values were calculated. Further, gradient-weighted class activation maps (Grad-CAM) were generated to localize the anatomy that contributed to the predictions. RESULTS: The accuracy, sensitivity, specificity, and precision of the CNN model were 95.1, 92.7, 97.0, and 95.9%, respectively. Grad-CAM analysis showed that the CNN model mainly identified root canal shapes converging into the apex to predict the C-shaped canals, while the root furcation was predominantly used for predicting the non-C-shaped canals. CONCLUSIONS: The deep-learning system had significant accuracy in predicting C-shaped canals of mandibular second molars on panoramic radiographs.

Reduction of Squalene Epoxidase by Cholesterol Accumulation Accelerates Colorectal Cancer Progression and Metastasis.

BACKGROUND & AIMS: Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is suggested as a proto-oncogene. Paradoxically, SQLE is degraded by excess cholesterol, and low SQLE is associated with aggressive colorectal cancer (CRC). Therefore, we studied the functional consequences of SQLE reduction in CRC progression. METHODS: Gene and protein expression data and clinical features of CRCs were obtained from public databases and 293 human tissues, analyzed by immunohistochemistry. In vitro studies showed underlying mechanisms of CRC progression mediated by SQLE reduction. Mice were fed a 2% high-cholesterol or a control diet before and after cecum implantation of SQLE genetic knockdown/control CRC cells. Metastatic dissemination and circulating cancer stem cells were demonstrated by in vivo tracking and flow cytometry analysis, respectively. RESULTS: In vitro studies showed that SQLE reduction helped cancer cells overcome constraints by inducing the epithelial-mesenchymal transition required to generate cancer stem cells. Surprisingly, SQLE interacted with GSK3ß and p53. Active GSK3ß contributes to the stability of SQLE, thereby increasing cell cholesterol content, whereas SQLE depletion disrupted the GSK3ß/p53 complex, resulting in a metastatic phenotype. This was confirmed in a spontaneous CRC metastasis mice model, where SQLE reduction, by a high-cholesterol regimen or genetic knockdown, strikingly promoted CRC aggressiveness through the production of migratory cancer stem cells. CONCLUSIONS: We showed that SQLE reduction caused by cholesterol accumulation aggravates CRC progression via the activation of the ß-catenin oncogenic pathway and deactivation of the p53 tumor suppressor pathway. Our findings provide new insights into the link between cholesterol and CRC, identifying SQLE as a key regulator in CRC aggressiveness and a prognostic biomarker.

Coiled-coil domain containing 50-V2 protein positively regulates neurite outgrowth.

The coiled-coil domain containing 50 (CCDC50) protein is a phosphotyrosine-dependent signalling protein stimulated by epidermal growth factor. It is highly expressed in neuronal cells in the central nervous system; however, the roles of CCDC50 in neuronal development are largely unknown. In this study, we showed that the depletion of CCDC50-V2 impeded the neuronal development process, including arbor formation, spine density development, and axonal outgrowth, in primary neurons. Mechanistic studies revealed that CCDC50-V2 positively regulated the nerve growth factor receptor, while it downregulated the epidermal growth factor receptor pathway. Importantly, JNK/c-Jun activation was found to be induced by the CCDC50-V2 overexpression, in which the interaction between CCDC50-V2 and JNK2 was also observed. Overall, the present study demonstrates a novel mechanism of CCDC50 function in neuronal development and provides new insight into the link between CCDC50 function and the aetiology of neurological disorders.

Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families.

Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy characterized by multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. Most patients with LGS do not respond well to drug treatment and show poor long-term prognosis. Approximately 30% of patients without brain abnormalities have unidentifiable causes. Therefore, accurate diagnosis and treatment of LGS remain challenging. To identify causative mutations of LGS, we analyzed the whole-exome sequencing data of 17 unrelated Korean families, including patients with LGS and LGS-like epilepsy without brain abnormalities, using the Genome Analysis Toolkit. We identified 14 mutations in 14 genes as causes of LGS or LGS-like epilepsy. 64 percent of the identified genes were reported as LGS or epilepsy-related genes. Many of these variations were novel and considered as pathogenic or likely pathogenic. Network analysis was performed to classify the identified genes into two network clusters: neuronal signal transmission or neuronal development. Additionally, knockdown of two candidate genes with insufficient evidence of neuronal functions, SLC25A39 and TBC1D8, decreased neurite outgrowth and the expression level of MAP2, a neuronal marker. These results expand the spectrum of genetic variations and may aid the diagnosis and management of individuals with LGS.

Prevalence, Antibiotic-Resistance, and Virulence Characteristics of Vibrio parahaemolyticus in Restaurant Fish Tanks in Seoul, South Korea.

Vibrio parahaemolyticus is a marine bacterium that causes foodborne diarrhea. Many seafood restaurants keep live fish and shellfish in fish tanks for use in raw seafood dishes; thus, the present study aimed to investigate the prevalence, antibiotic-resistance, and virulence characteristics exhibited by V. parahaemolyticus detected in restaurant fish-tank water samples collected in Seoul, South Korea. Fish-tank water samples were collected from 69 restaurants in Seoul, and screened for the presence of V. parahaemolyticus via both a commercial detection kit, and a real-time polymerase chain reaction (RT-PCR) to detect the toxR gene. Antibiotic susceptibility and virulence determinants of V. parahaemolyticus isolates were evaluated and identified using standard disk-diffusion and RT-PCR methods, respectively. Thirty-five (50.7%) of the 69 analyzed water samples were found to be contaminated with V. parahaemolyticus. Those isolates were most often resistant to ampicillin (51.4% of isolates), followed by amikacin and tetracycline (11.4%), and ceftazidime (8.6%). Thirty (85.7%) out of the 35 isolates carried all four cytotoxicity-inducing type III secretion system 1 (T3SS1) genes [specifically, 34 (97.1%), 33 (94.3%), 35 (100%), and 32 (91.4%) isolates carried genes encoding the VP1670, VP1686, VP1689, and VP1694 T3SS1 proteins, respectively]. The type VI secretion systems (T6SS1 and T6SS2) genes were also detected in 11 (31.4%) and 27 (77.1%) isolates, respectively. However, virulence determinants such as the hemolysin (tdh and trh), urease (ureC), T3SS2α, or T3SS2ß genes that are known to be associated with enterotoxicity were not detected in all isolates. Although some known major virulence genes were not detected in the V. parahaemolyticus isolates, the results of this study indicate that restaurant fish tanks are a potential source of antibiotic-resistant V. parahaemolyticus. The presented data support the need for strict guidelines to regulate the maintenance of restaurant fish tanks to prevent antibiotic-resistant foodborne vibriosis.

A Novel X-Linked Variant of IQSEC2 is Associated with Lennox-Gastaut Syndrome and Mild Intellectual Disability in Three Generations of a Korean Family.

Aim: Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy with multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. However, LGS-related genes are largely unknown. To identify causative genes related to LGS, we collected and analyzed data from a three-generation Korean family in which one member had LGS and two had intellectual disability. Methods: Genomic DNAs were extracted from blood samples of all participants and used in whole-exome sequencing (WES). Genetic variants were detected by the Genome Analysis Toolkit and confirmed by Sanger sequencing. Variant pathogenicity was evaluated by prediction programs and the American College of Medical Genetics criteria. The LGS patient had generalized slow spike-and-wave discharges, multiple types of seizures, and developmental delay. Results: Analyses of the WES data from the family revealed a novel variant (c.1048G>A, p.Ala350Thr) in the IQ motif and Sec7 domain 2 (IQSEC2). This variant is within a highly evolutionarily conserved IQ-like motif, indicating a decrease in the calmodulin-binding capacity or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid transmission. The hemizygous variant in the male with LGS was a maternally inherited X-linked variant from the heterozygous maternal grandmother and mother, both of whom had intellectual disability. Conclusion: These findings indicate that the variant of IQSEC2 triggered both LGS and intellectual disability dependent on sex in this family. We report a novel X-linked inherited IQSEC2 variant for LGS and intellectual disability, which enhances the spectrum of variants in the IQ-like motif of IQSEC2.

TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway.

Autophagy, an intracellular system of degrading damaged organelles and misfolded proteins, is essential for cancer cell survival. Despite the progress made towards understanding the mechanism, identification of novel autophagy regulators presents a major obstacle in developing anticancer therapies. Here, we examine the association between the TOR signaling pathway regulator-like (TIPRL) protein and autophagy in malignant transformation of tumors. We show that TIPRL upregulation in non-small cell lung cancer (NSCLC) potentiated autophagy activity and enabled autophagic clearance of metabolic and cellular stress, conferring a survival advantage to cancer cells. Importantly, the interaction of TIPRL with eukaryotic initiation factor 2α (eIF2α) led to eIF2α phosphorylation and activation of the eIF2α-ATF4 pathway, thereby inducing autophagy. Conversely, TIPRL depletion increased apoptosis by reducing autophagic clearance, which was markedly enhanced in TIPRL-depleted A549 xenografts treated with 2-deoxy-D-glucose. Overall, the study indicated that TIPRL is a potential regulator of autophagy and an important drug target for lung cancer therapy.

The positive correlation of TIPRL with LC3 and CD133 contributes to cancer aggressiveness: potential biomarkers for early liver cancer.

Studies have reported dysregulation of TIPRL, LC3 and CD133 in liver cancer tissues. However, their respective relationships to liver cancer and roles as biomarkers for prognosis and diagnosis of liver cancer have never been studied. Here we report that the level of TIPRL is significantly correlated with levels of LC3 (Spearman r = 0.9) and CD133 (r = 0.7) in liver cancer tissues. We observed significant upregulations of TIPRL, LC3 and CD133 in hepatocellular carcinomas (HCCs) compared with adjacent normal tissues. Importantly, TIPRL, tested among additional variables, showed a significant impact on the prognosis of HCC patients. TIPRL knockdown significantly reduced expressions of LC3, CD133, stemness-related genes, as well as viability and stemness of liver cancer cell-lines, which were promoted by ectopic TIPRL expression. Either alone or as a combination, TIPRL, LC3 and CD133 showed significant values of area under the curve (AUC) and sensitivity/specificity in early liver cancer tissues. Furthermore, the statistical association and the diagnostic efficacies of TIPRL, LC3 and CD133 in HCC tissues were confirmed in a different IHC cohort. This data demonstrates that the complex involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness can together or individually serve as potential biomarkers for the early detection of liver cancer.

Novel S-Bend Resonator Based on a Multi-Mode Waveguide with Mode Discrimination for a Refractive Index Sensor.

In this paper, a multi-mode waveguide-based optical resonator is proposed for an integrated optical refractive index sensor. Conventional optical resonators have been studied for single-mode waveguide-based resonators to enhance the performance, but mass production is limited owing to the high fabrication costs of nano-scale structures. To overcome this problem, we designed an S-bend resonator based on a micro-scale multi-mode waveguide. In general, multi-mode waveguides cannot be utilized as optical resonators, because of a performance degradation resulting from modal dispersion and an output transmission with multi-peaks. Therefore, we exploited the mode discrimination phenomenon using the bending loss, and the resulting S-bend resonator yielded an output transmission without multi-peaks. This phenomenon is utilized to remove higher-order modes efficiently using the difference in the effective refractive index between the higher-order and fundamental modes. As a result, the resonator achieved a Q-factor and sensitivity of 2.3 × 103 and 52 nm/RIU, respectively, using the variational finite-difference time-domain method. These results show that the multi-mode waveguide-based S-bend resonator with a wide line width can be utilized as a refractive index sensor.

Corrigendum: Corrections to the funding. Quantification of the tug-back by measuring the pulling force and micro computed tomographic evaluation.

[This corrects the article on p. 273 in vol. 42, PMID: 29142875.].

Quantification of the tug-back by measuring the pulling force and micro computed tomographic evaluation.

OBJECTIVES: The aims of this study were to quantify tug-back by measuring the pulling force and investigate the correlation of clinical tug-back pulling force with in vitro gutta-percha (GP) cone adaptation score using micro-computed tomography (µCT). MATERIALS AND METHODS: Twenty-eight roots from human single-rooted teeth were divided into 2 groups. In the ProTaper Next (PTN) group, root canals were prepared with PTN, and in the ProFile (PF) group, root canals were prepared using PF (n = 14). The degree of tug-back was scored after selecting taper-matched GP cones. A novel method using a spring balance was designed to quantify the tug-back by measuring the pulling force. The correlation between tug-back scores, pulling force, and percentage of the gutta-percha occupied area (pGPOA) within apical 3 mm was investigated using µCT. The data were analyzed using Pearson's correlation analysis, one-way analysis of variance (ANOVA) and Tukey's test. RESULTS: Specimens with a strong tug-back had a mean pulling force of 1.24 N (range, 0.15-1.70 N). This study showed a positive correlation between tug-back score, pulling force, and pGPOA. However, there was no significant difference in these factors between the PTN and PF groups. Regardless of the groups, pGPOA and pulling force were significantly higher in the specimens with a higher tug-back score (p < 0.05). CONCLUSIONS: The degree of subjective tug-back was a definitive determinant for master cone adaptation in the root canal. The use of the tug-back scoring system and pulling force allows the interpretation of subjective tug-back in a more objective and quantitative manner.

Novel indazole-based small compounds enhance TRAIL-induced apoptosis by inhibiting the MKK7-TIPRL interaction in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors. Although various treatments, such as surgery and chemotherapy, have been developed, a novel alternative therapeutic approach for HCC therapy is urgently needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent, but many cancer cells are resistant to TRAIL-induced apoptosis. To help overcome TRAIL resistance in HCC cancer cells, we have identified novel chemical compounds that act as TRAIL sensitizers. We first identified the hit compound, TRT-0002, from a chemical library of 6,000 compounds using a previously developed high-throughput enzyme-linked immunosorbent assay (ELISA) screening system, which was based on the interaction of mitogen-activated protein kinase kinase 7 (MKK7) and TOR signaling pathway regulator-like (TIPRL) proteins and a cell viability assay. To increase the efficacy of this TRAIL sensitizer, we synthesized 280 analogs of TRT-0002 and finally identified two lead compounds (TRT-0029 and TRT-0173). Co-treating cultured Huh7 cells with either TRT-0029 or TRT-0173 and TRAIL resulted in TRAIL-induced apoptosis due to the inhibition of the MKK7-TIPRL interaction and subsequent phosphorylation of MKK7 and c-Jun N-terminal kinase (JNK). In vivo, injection of these compounds and TRAIL into HCC xenograft tumors resulted in tumor regression. Taken together, our results suggest that the identified lead compounds serve as TRAIL sensitizers and represent a novel strategy to overcome TRAIL resistance in HCC.