Association of the Low-density Lipoprotein Cholesterol/High-density Lipoprotein Cholesterol Ratio with Glecaprevir-pibrentasvir Treatment.

Objective The change in serum lipid levels by direct-acting antiviral (DAA) treatment for chronic hepatitis C varies depending on the type of DAA. How the lipid level changes induced by glecaprevir-pibrentasvir (G/P) treatment contribute to the clinical outcome remains unclear. We conducted a prospective observational study to evaluate the effectiveness of G/P treatment and the lipid level changes. Methods The primary endpoint was a sustained virologic response at 12 weeks (SVR12). The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and LDL-C/HDL-C (L/H) ratio were measured every two weeks. Patients This study included 101 patients. Seventeen cases of liver cirrhosis and nine cases of DAA retreatment were registered. The G/P treatment period was 8 weeks in 74 cases and 12 weeks in 27 cases. Results SVR12 was evaluated in 96 patients. The rate of achievement of SVR12 in the evaluable cases was 100%. We found significantly elevated TC and LDL-C levels over the observation period compared to baseline. The serum levels of HDL-C did not change during treatment but were significantly increased after treatment compared to baseline. The L/H ratio was significantly increased two weeks after the start of treatment but returned to the baseline after treatment. Conclusion The primary endpoint of the SVR12 achievement rate was 100%. G/P treatment changed the serum lipid levels. Specifically, the TC and LDL-C levels increased during and after treatment, and the HDL-C levels increased after treatment. G/P treatment may be associated with a reduced thrombotic risk. Therefore, validation in large trials is recommended.

Simulation of orthodontic tooth movement during activation of an innovative design of closing loop using the finite element method.

INTRODUCTION: Although many attempts have been made to study the mechanical behavior of closing loops, most have been limited to analyses of the magnitude of forces and moments acting on the end of the closing loop. The objectives of this study were to simulate orthodontic tooth movement during the activation of a newly designed closing loop combined with a gable bend and to investigate the optimal loop activation condition to achieve the desired tooth movement. METHODS: We constructed a 3-dimensional model of maxillary dentition reproducing the state wherein a looped archwire combined with a gable bend was engaged in brackets and tubes. Orthodontic tooth movements were simulated for both anterior and posterior teeth while varying the degree of gable bend using the finite element method. RESULTS: The incorporation of a 5° gable bend into the newly designed closing loop produced lingual crown tipping for the central incisor and bodily movement for the first molar. The incorporation of 10° and 15° gable bends produced bodily movement and root movement, respectively, for the central incisor and distal tipping for the first molar. CONCLUSIONS: Torque control of the anterior teeth and anchorage control of the posterior teeth can be carried out effectively and simply by reducing by half the thickness of a teardrop loop with a height of 10 mm and a 0.019 × 0.025-in cross-section, to a distance of 3 mm from its apex, and by incorporating various degrees of gable bend into the loop corresponding to the treatment plan.

Numeric simulation model for long-term orthodontic tooth movement with contact boundary conditions using the finite element method.

INTRODUCTION: Although many attempts have been made to simulate orthodontic tooth movement using the finite element method, most were limited to analyses of the initial displacement in the periodontal ligament and were insufficient to evaluate the effect of orthodontic appliances on long-term tooth movement. Numeric simulation of long-term tooth movement was performed in some studies; however, neither the play between the brackets and archwire nor the interproximal contact forces were considered. The objectives of this study were to simulate long-term orthodontic tooth movement with the edgewise appliance by incorporating those contact conditions into the finite element model and to determine the force system when the space is closed with sliding mechanics. METHODS: We constructed a 3-dimensional model of maxillary dentition with 0.022-in brackets and 0.019 × 0.025-in archwire. Forces of 100 cN simulating sliding mechanics were applied. The simulation was accomplished on the assumption that bone remodeling correlates with the initial tooth displacement. RESULTS: This method could successfully represent the changes in the moment-to-force ratio: the tooth movement pattern during space closure. CONCLUSIONS: We developed a novel method that could simulate the long-term orthodontic tooth movement and accurately determine the force system in the course of time by incorporating contact boundary conditions into finite element analysis. It was also suggested that friction is progressively increased during space closure in sliding mechanics.

Serum HER2 as an adjunct to assess HER2 status for advanced gastric cancer: A prospective multicenter trial (SHERLOCK).

BACKGROUND: Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity of gastric cancer can be an obstacle to accurate HER2 assessment. Serum HER2, concentrations of the HER2 extracellular domain shed into the bloodstream, has a potential to compensate HER2 immunohistochemistry (IHC) but has not been scrutinized in gastric cancer. This study sought to explore the clinical utility of serum HER2 in gastric cancer. METHODS: We performed a prospective multicenter trial (SHERLOCK trial) involving patients with all-stage gastric or gastro-esophageal junction cancer. Serum HER2 was measured using direct chemiluminescence while tissue HER2 status was determined using IHC and fluorescent in situ hybridization. For stage IV cases, concordance between local and central laboratories in tissue HER2 assessment was also evaluated. RESULTS: Of 224 patients enrolled, both tissue HER2 status and serum HER2 levels were successfully determined in 212 patients and 21% (45/212) were tissue HER2-positive. Serum HER2 levels, ranged from 4.5 to 148.0 ng/ml (median 10.3), correlated with tissue HER2 status (p = 0.003). At a cut-off level of 28.0 ng/ml determined by receiver operating characteristics analysis, sensitivity, specificity, positive and negative predictive values of serum HER2 were 22.6%, 100%, 100% and 82.3%, respectively. All nine cases with elevated serum HER2 were tissue HER2-positive stage IV cases. Among 61 stage IV cases, the agreement rate for IHC scoring between the local and the central laboratories was 82% and tissue HER2 judgment was conflicting in five (8.2%) cases. Of these five cases, four were confirmed as false-negative and two of these four patients demonstrated elevated serum HER2. CONCLUSIONS: Serum HER2 levels correlated with tissue HER2 status in gastric cancer. Although the low sensitivity is a drawback, serum HER2 might be a useful adjunct tool to detect tissue HER2 false-negative gastric cancer.

Genetic and epigenetic characteristics of gastric cancers with JC virus T-antigen.

AIM: To clarify the significance of JC virus (JCV) T-antigen (T-Ag) expression in human gastric cancer. METHODS: We investigated the relationship between T-Ag detected by immunohistochemistry and Epstein-Barr virus (EBV) infection, microsatellite instability (MSI), and genetic and epigenetic alterations in gastric cancers. Mutations in the p53, beta-catenin, KRAS, BRAF, PIK3CA genes were analyzed by polymerase chain reaction (PCR)-single strand conformation polymorphism and DNA sequencing. Allelic losses were determined by PCR at 7 microsatellite loci. Aberrant DNA methylation was analyzed by MethyLight assay. RESULTS: JCV T-Ag protein expression was found in 49% of 90 gastric cancer tissues. T-Ag positivity was not correlated with clinicopathological characteristics. T-Ag expression was detected in a similar percentage of EBV positive cancers (4 of 9, 44%) and EBV negative cancers (35 of 73, 48%). T-Ag expression was detected in a significantly lower percentage of MSI-H cancers (14%) than in non MSI-H cancers (55%, P = 0.005). T-Ag expression was detected in a significantly higher percentage of cancers with nuclear/cytoplasmic localization of beta-catenin (15 of 21, 71%) than in cancers without (42%, P = 0.018). p53 mutations were detected in a significantly lower percentage of T-Ag positive cancers (32%) than in T-Ag negative cancers (57%, P = 0.018). T-Ag positive gastric cancers showed a significant increase in the allelic losses and aberrant methylation compared with T-Ag negative gastric cancers (P = 0.008 and P = 0.003). CONCLUSION: The results suggest that JCV T-Ag is involved in gastric carcinogenesis through multiple mechanisms of genetic and epigenetic alterations.

Juvenile polyposis complicated with protein losing gastropathy.

A male patient with chronic bloody stool was diagnosed as juvenile polyposis at the age of 28. He had thirty to forty colonic polyps and some were removed endoscopically, while gastric polyps were too numerous to intervene. As the polyposis advanced gradually, the patient developed intractable anemia and serious hypoproteinemia. Albumin scintigram revealed protein losing gastropathy due to progressive gastric polyposis. Total gastrectomy was carried out at the age of 34 and the patient has achieved remarkable and sustainable improvement.

Transcriptional silencing of Dickkopf gene family by CpG island hypermethylation in human gastrointestinal cancer.

AIM: To clarify alterations of Dickkopfs (Dkks) and Kremen2 (Krm2) in gastrointestinal cancer. METHODS: We investigated the expression profiles and epigenetic alterations of Dkks and Krm2 genes in gastrointestinal cancer using RT-PCR, tissue microarray analysis, and methylation specific PCR (MSP). Cancer cells were treated with the demethylating agent and/or histone deacetylase inhibitor. WST-8 assays and in vitro invasion assays after treatment with specific siRNA for those genes were performed. RESULTS: Dkks and Krm2 expression levels were reduced in a certain subset of the gastrointestinal cancer cell lines and cancer tissues. This was correlated with promoter hypermethylation. There were significant correlations between Dkks over-expression levels and beta-catenin over-expression in colorectal cancer. In colorectal cancers with beta-catenin over-expression, Dkk-1 expression levels were significantly lower in those with lymph node metastases than in those without. Down-regulation of Dkks expression by siRNA resulted in a significant increase in cancer cell growth and invasiveness in vitro. CONCLUSION: Down-regulation of the Dkks associated to promoter hypermethylation appears to be frequently involved in gastrointestinal tumorigenesis.

Correlation of laterally spreading type and JC virus with methylator phenotype status in colorectal adenoma.

Accurate frequencies of CpG island methylator phenotype (CIMP) have not been determined for laterally spreading tumors (LSTs) and other flat-type colorectal adenomas, and the role of JC virus T-antigen (T-Ag) in these tumors is unclear. We used MethyLight assay to analyze the relationship between CIMP status and clinicopathologic characteristics in tissue from 72 LST of granular-type (LST-G), 35 LST of nongranular-type (LST-NG), 54 protruded-type adenomas, and 89 colorectal cancers. We also investigated the relationship between CIMP status and T-Ag by immunohistochemistry. With the use of 5 markers for CIMP status, tumors were classified as CIMP-high (> or = 4/5 methylated promoters), CIMP-low (1/5 to 3/5 methylated promoters), or CIMP-0 (no methylated promoters). The proportion classified as CIMP-0 status was 5.6% for protruded-type adenoma, 17.1% for LST-NG, and 29.2% for LST-G (LST-G versus protruded-type adenoma, P = .001). CIMP-low status was established for 62.5% of LST-G, 74.3% of LST-NG, and 81.5% of protruded-type adenomas. CIMP-high status was established for 8.3% of LST-G, 8.6% of LST-NG, and 12.9% of protruded-type adenomas. The proportions of CIMP-low and CIMP-high status were not significantly different between the 3 groups. Multiple logistic analysis showed that LST-G appearance was the only significant factor for identifying CIMP-0 status. BRAF mutation was the only significant factor for identifying CIMP-high status. T-Ag expression increased with CIMP status and was not associated with macroscopic appearance. In conclusion, among colorectal adenomas, CIMP-high status was determined by BRAF mutation and not by macroscopic type, unlike CIMP-0. JC virus T-Ag may be important in determining methylator phenotype.