Comparison of diagnostic performance of two ultrasound risk stratification systems for thyroid nodules: a systematic review and meta-analysis.

OBJECTIVES: To assume the ideal cut-off values and diagnostic performance of two thyroid imaging reporting and data systems published by the Korean Thyroid Association/Korean Society of Thyroid Radiology (Korean TI-RADS) and the American Thyroid Association (ATA TI-RADS). METHODS: Eighteen studies with 25,422 patients from PubMed, SCOPUS, Embase, Web of Science, and Cochrane Library databases up to August 2022. True and false positive and negative values with characteristics were extracted. RESULTS: The highest area under the receiver operating characteristic curve (AUC) was 0.893 and 0.887 for Korean and ATA TI-RADS. High suspicion was judged as the best cut-off value with the highest AUC based on optimal sensitivity and specificity. In determining the risk of malignant thyroid nodules, high suspicion in Korean and ATA TI-RADS showed sensitivity as 71.3% and 73.5%, specificity as 7.9% and 86.4%, diagnostic odds ratios as 20.0289 and 20.9076, AUC as 0.893 and 0.887. There was no significant difference when directly comparing the diagnostic accuracy of both TI-RADS. CONCLUSION: The two risk stratification systems had good diagnostic performance with high AUC and no significant differences. The ideal cut-off can depend on the medical condition or thyroid nodules, because the changes of cut-off point may reciprocally alter sensitivity and specificity.

Concomitant Use of Proton Pump Inhibitors and Palbociclib Among Patients With Breast Cancer.

Importance: Proton pump inhibitors (PPIs) are commonly used drugs to relieve gastrointestinal tract symptoms, but their acid-inhibitory action negatively affects the bioavailability and clinical outcomes of orally administered concomitant drugs. Objective: To identify the clinical outcomes of patients with advanced breast cancer who concomitantly use PPIs and palbociclib. Design, Setting, and Participants: This retrospective cohort study used nationwide claims data between November 1, 2016, and July 31, 2021, in South Korea. Patients with breast cancer receiving palbociclib between November 1, 2017, and July 31, 2020, were identified. Patients whose prescriptions for palbociclib and PPI overlapped by at least 33% were classified into a concomitant PPI group. Patients who never received PPI during the palbociclib treatment period were classified into a nonconcomitant PPI group. Patients were selected through 1:3 propensity score matching for analyses. Exposures: Concomitant use of PPIs with palbociclib. Main Outcomes and Measures: Time to progression and death. These outcomes were presented as progression-free survival (PFS) and overall survival (OS) and were analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to estimate the hazard ratio (HR) of concomitant PPI use associated with clinical PFS and/or OS. Results: A total of 344 women were included in the concomitant PPI group and 966 in the nonconcomitant PPI group. Among 1310 patients identified after matching, 1108 (84.6%) were older than 50 years; 1111 (84.8%) were treated with letrozole and anastrozole (endocrine sensitive); and 199 (15.2%) were treated with fulvestrant (endocrine resistant). The median clinical PFS in the concomitant PPI group was shorter than that of the nonconcomitant PPI group (25.3 [95% CI, 19.6-33.0] vs 39.8 [95% CI, 34.9 to not applicable] months; P < .001), and the HR was 1.76 (95% CI, 1.46-2.13). Concomitant use of PPI was also associated with shorter OS (HR, 2.71 [95% CI, 2.07-3.53]). Both clinical PFS and OS in the concomitant PPI group were consistently poor in patients receiving endocrine-sensitive and endocrine-resistant treatment. Conclusions and Relevance: These findings suggest that concomitant use of PPIs with palbociclib may hinder the complete therapeutic benefits of palbociclib in patients with breast cancer.

Thrap3 promotes nonalcoholic fatty liver disease by suppressing AMPK-mediated autophagy.

Autophagy functions in cellular quality control and metabolic regulation. Dysregulation of autophagy is one of the major pathogenic factors contributing to the progression of nonalcoholic fatty liver disease (NAFLD). Autophagy is involved in the breakdown of intracellular lipids and the maintenance of healthy mitochondria in NAFLD. However, the mechanisms underlying autophagy dysregulation in NAFLD remain unclear. Here, we demonstrate that the hepatic expression level of Thrap3 was significantly increased in NAFLD conditions. Liver-specific Thrap3 knockout improved lipid accumulation and metabolic properties in a high-fat diet (HFD)-induced NAFLD model. Furthermore, Thrap3 deficiency enhanced autophagy and mitochondrial function. Interestingly, Thrap3 knockout increased the cytosolic translocation of AMPK from the nucleus and enhanced its activation through physical interaction. The translocation of AMPK was regulated by direct binding with AMPK and the C-terminal domain of Thrap3. Our results indicate a role for Thrap3 in NAFLD progression and suggest that Thrap3 is a potential target for NAFLD treatment.

Economic Burden of Recurrence in Completely Resected Stage IB-IIIA Non-Small Cell Lung Cancer: A Retrospective Study Using Nationwide Claims Data of South Korea.

INTRODUCTION: Although many patients with early stage non-small cell lung cancer (NSCLC) experience recurrence despite complete resection, few studies have reported on the corresponding economic burden. This study aimed to understand the economic impact of recurrence by measuring healthcare costs and resource utilization in patients with recurrent stage IB-IIIA NSCLC. METHODS: Using Health Insurance Review and Assessment claims data from South Korea, we included patients who underwent complete resection for stage IB-IIIA NSCLC during the index period (January 1, 2012, to October 31, 2018). Patients who experienced recurrence were matched with those who did not using 1:1 propensity score (PS) matching. The mean healthcare costs and resource utilization were analyzed from the date of complete resection to the last claims for cancer treatment. A generalized linear model (GLM) was used to estimate the impact of covariates on healthcare costs. A difference-in-difference (DID) analysis was conducted to analyze the healthcare costs between the two groups before and after recurrence. RESULTS: Patients with recurrence incurred higher healthcare costs, particularly in outpatient settings. The cost of targeted therapy and immune checkpoint inhibitors primarily contributed to cost differences, and medication costs increased over time after complete resection. Patients with recurrence were also hospitalized more frequently (9.3 vs. 5.0, p < 0.0001) for a longer period (74 days vs. 42 days, p < 0.0001) than those without recurrence. GLM analysis showed that the total cost was 2.31-fold higher in patients with recurrence (95% confidence interval: 2.19-2.44). The DID analysis showed significantly increased total costs in patients with recurrence (ß = 26,269, p < 0.0001), which was mostly attributed to medication costs (ß = 17,951, p < 0.0001). CONCLUSION: Recurrence of completely resected NSCLC leads to a substantial increase in healthcare costs and resource utilization. The results of this study show the economic burden of recurrence, which may help future economic analyses and resource allocation.

Diagnostic Performance of ACR and Kwak TI-RADS for Benign and Malignant Thyroid Nodules: An Update Systematic Review and Meta-Analysis.

(1) Background: To determine the optimal cut-off values of two risk stratification systems to discriminate malignant thyroid nodules and to compare the diagnostic performance; (2) Methods: True and false positive and negative data were collected, and methodological quality was assessed for forty-six studies involving 39,085 patients; (3) Results: The highest area under the receiver operating characteristic (ROC) curve (AUC) of ACR and Kwak TI-RADS were 0.875 and 0.884. Based on the optimal sensitivity and specificity, the highest accuracy values of ROC curves or diagnostic odds ratios (DOR) were taken as the cut-off values for TR4 (moderate suspicious) and 4B. The sensitivity, specificity, DOR, and AUC by ACR (TR4) and Kwak TI-RADS (4B) for malignancy risk stratification of thyroid nodules were 94.3% and 96.4%; 52.2% and 53.7%; 17.5185 and 31.8051; 0.786 and 0.884, respectively. There were no significant differences in diagnostic accuracy in any of the direction comparisons of the two systems; (4) Conclusions: ACR and Kwak TI-RADS had good diagnostic performances (AUCs > 85%). Although we determined the best cut-off values in individual risk stratification systems based on statistical assessment, clinicians can adjust the optimal cut-off value according to the clinical purpose of the ultrasonography because raising or lowering cut-points leads to reciprocal changes in sensitivity and specificity.

Chryseobacterium vaccae sp. nov., isolated from raw cow's milk.

Strain CA7T, a Gram-stain-negative, non-motile, non-spore-forming, aerobic and rod-shaped bacterial strain, was isolated from raw cow's milk collected from a farm affiliated with Chung-Ang University, Anseong, Korea, and characterized by a polyphasic approach. Optimal growth of strain CA7T was observed on tryptic soy agar at 30 °C and pH 7.0 with 0 % NaCl. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain CA7T belonged to the genus Chryseobacterium. The most closely related strains (16S rRNA gene sequence similarity indicated in parentheses), based on the phylogenetic analysis, were Chryseobacterium rhizosphaerae KCTC 22548T (98.08 %), Chryseobacterium nakagawai CCUG 60563T (98.61 %), Chryseobacterium jejuense KACC 12501T (97.85 %) and Chryseobacterium aurantiacum KCTC 62135T (97.78 %). Whole genome sequencing indicated that the genome size was 5 125 723 bp and had a DNA G+C content of 37.4 mol%. Average nucleotide identity values for strain CA7T with C. rhizosphaerae, C. nakagawai, C. jejuense, C. aurantiacum, and the type species of the genus Chryseobacterium, C. gleum, were 80.2, 79.8, 79.8, 79.6 and 80.4 %, respectively. The digital DNA-DNA hybridization values of CA7T compared to C. rhizosphaerae, C. nakagawai, C. jejuense, C. aurantiacum and C. gleum were 24.1, 23.9, 23.9, 23.7 and 24.3 %, respectively. The major fatty acids were iso-C15 : 0, summed feature 9 (iso-C17 : 1 ω9c and/or C16 : 0 10-methyl), iso-C17 : 0 3-OH and summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1 ω7c). Menaquinone-6 was the only respiratory quinone. The major polar lipid was phosphatidylethanolamine. Based on this polyphasic taxonomic study, strain CA7T represents a novel species of the genus Chryseobacterium for which the name Chryseobacterium vaccae sp. nov. is proposed. The type strain is CA7T (=KACC 21402T=JCM 33749T).

Acinetobacter pullorum sp. nov., Isolated from Chicken Meat.

A bacterial strain, designated B301T and isolated from raw chicken meat obtained from a local market in Korea, was characterized and identified using a polyphasic taxonomic approach. Cells were gram-negative, non-motile, obligate-aerobic coccobacilli that were catalase-positive and oxidase-negative. The optimum growth conditions were 30°C, pH 7.0, and 0% NaCl in tryptic soy broth. Colonies were round, convex, smooth, and cream-colored on tryptic soy agar. Strain B301T has a genome size of 3,102,684 bp, with 2,840 protein-coding genes and 102 RNA genes. The 16S rRNA gene analysis revealed that strain B301T belongs to the genus Acinetobacter and shares highest sequence similarity (97.12%) with A. celticus ANC 4603T and A. sichuanensis WCHAc060041T. The average nucleotide identity and digital DNA-DNA hybridization values for closely related species were below the cutoff values for species delineation (95-96% and 70%, respectively). The DNA G+C content of strain B301T was 37.0%. The major respiratory quinone was Q-9, and the cellular fatty acids were primarily summed feature 3 (C16:1 ω6c/C16:1 ω7c), C16:0, and C18:1 ω9c. The major polar lipids were phosphatidylethanolamine, diphosphatidyl-glycerol, phosphatidylglycerol, and phosphatidyl-serine. The antimicrobial resistance profile of strain B301T revealed the absence of antibiotic-resistance genes. Susceptibility to a wide range of antimicrobials, including imipenem, minocycline, ampicillin, and tetracycline, was also observed. The results of the phenotypic, chemotaxonomic, and phylogenetic analyses indicate that strain B301T represents a novel species of the genus Acinetobacter, for which the name Acinetobacter pullorum sp. nov. is proposed. The type strain is B301T (=KACC 21653T = JCM 33942T).

Chryseobacterium aureum sp. nov., isolated from the Han River, Republic of Korea.

A Gram-stain-negative, yellow-pigmented, non-motile, non-spore-forming, aerobic and rod-shaped bacterial strain, designated 17S1E7T, was isolated from the Han River, Republic of Korea, and characterized by polyphasic taxonomy analyses. Strain 17S1E7T grew optimally on tryptic soy agar at 37 °C and pH 7.0 in the absence of NaCl. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain 17S1E7T belonged to the genus Chryseobacterium and was most closely related to Chryseobacterium culicis DSM 23031T (98.54 %). The average nucleotide identity value of strain 17S1E7T was 91.1 % to Chryseobacterium culicis DSM 23031T, which was lower than the cut-off of 95-96 %. The DNA G+C content of strain 17S1E7T was 37.4 mol%. Flexirubin-type pigments were produced. The predominant respiratory quinone was menaquinone 6. The major fatty acids of strain 17S1E7T were iso-C15 : 0, summed feature 9 (iso-C17 : 1ω9c and/or C16 : 0 10-methyl), iso-C17 : 0 3-OH and summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1ω7c). The predominant polar lipid was phosphatidylethanolamine. Based on polyphasic taxonomy data, strain 17S1E7T represents a novel species of the genus Chryseobacterium, for which the name Chryseobacterium aureum sp. nov. is proposed. The type strain is 17S1E7T (=KACC 19920T=JCM 33165T).

Biosorption of radioactive cesium from contaminated water by microalgae Haematococcus pluvialis and Chlorella vulgaris.

The biosorption properties of water-soluble radioactive cesium (137Cs) by microalga Haematococcus pluvialis were evaluated with different cell conditions, and its cesium-uptake rate was compared with that by other microalgae, Chlorella vulgaris and Anabaena sp. Photo-induced H. pluvialis red cyst rapidly removed radioactive cesium from the solution by bioaccumulation. We showed that the effectiveness of 137Cs uptake is dependent on the specific cell condition of even the same microalgal species. While the H. pluvialis red cyst removed almost 95% of the soluble 137Cs in 48 h, both H. pluvialis intermediate cells and C. vulgaris showed 90% uptake efficiency of 137Cs with slow uptake rate. The energy dispersive spectrometer data demonstrated that the cesium uptake acceleration by inducing astaxanthin in H. pluvialis red cyst involves the cesium accumulation through the potassium transport channel. The long-term monitoring experiments of the cesium uptake showed that only 40% of 137Cs remained in collapsed H. pluvialis cell fragments after 12 months.

Dopamine and Cu+/2+ can induce oligomerization of α-synuclein in the absence of oxygen: Two types of oligomerization mechanisms for α-synuclein and related cell toxicity studies.

α-Synuclein oligomers can induce neurotoxicity and are implicated in Parkinson's disease etiology and disease progression. Many studies have reported α-synuclein oligomerization by dopamine (DA) and transition metal ions, but few studies provide insight into joint influences of DA and Cu2+ . In this study, DA and Cu2+ were coadministered aerobically to measure α-synuclein oligomerization under these conditions. In the presence of oxygen, DA induced α-synuclein oligomerization in a dose-dependent manner. Cu+/2+ did not effect oligomerization in such a manner in the presence of DA. By electrophoresis, Cu2+ was found easily to induce oligomerization with DA. This implies that oligomerization invoked by DA is reversible in the presence of Cu2+, which appears to be mediated by noncovalent bond interactions. In the absence of oxygen, DA induced less oligomerization of α-synuclein, whereas DA/Cu2+ induced aerobic-level amounts of oligomers, suggesting that DA/Cu2+ induces oligomerization independent of oxygen concentration. Radical species were detected through electron paramagnetic resonance (EPR) spectroscopic analysis arising from coincubation of DA/Cu2+ with α-synuclein. Redox reactions induced by DA/Cu2+ were observed in multimer regions of α-synuclein oligomers through NBT assay. Cellular toxicity results confirm that, for normal and hypoxic conditions, copper or DA/Cu2+ can induce cell death, which may arise from copper redox chemistry. From these results, we propose that DA and DA/Cu2+ induce different mechanisms of α-synuclein oligomerization, cross-linking with noncovalent (or reversible covalent) bonding vs. likely radical-mediated covalent modification.

The regulatory mechanism of melanogenesis by FTY720, a sphingolipid analogue.

We previously reported that sphingosine-1-phosphate (S1P) decreases melanin synthesis via extracellular signal-regulated protein kinase (ERK) activation and microphthalmia-associated transcription factor (MITF) degradation. Although FTY720 is an S1P structural analogue, the effects of FTY720 on melanogenesis are not completely understood. Thus, we investigated the influence of FTY720 on melanin synthesis in a spontaneously immortalized mouse melanocyte cell line (Mel-Ab). FTY720 inhibited melanin synthesis in a concentration-dependent manner. Further, FTY720 has a different signal transduction mechanism to regulate melanogenesis from the S1P-induced signalling pathway. Our results showed that FTY720 down-regulated MITF and tyrosinase expression without ERK activation. MITF, the master regulator of pigmentation, is a target for the Wnt signalling pathway, including glycogen synthase kinase 3ß (GSK3ß) and ß-catenin. Thus, the influence of FTY720 on GSK3ß and ß-catenin was further investigated. Decreased MITF and tyrosinase were associated with a reduction of ß-catenin protein and mRNA levels. Decreased ß-catenin expression by FTY720 may down-regulate expression of MITF, which finally reduces melanin synthesis.

Enhanced effects of citrate on UVB-induced apoptosis of B16 melanoma cells.

Ultraviolet (UV) radiation is a major risk factor for the development of melanoma. Recent studies have reported that the intake of citrate-containing juices may reduce the risk of cancer. Thus, we investigated the effects of citrate on UVB-irradiated B16 murine melanoma cells. B16 cells had more evident apoptotic features with the combination of citrate/UVB than by citrate or UVB alone; cell death of HaCaT human keratinocytes was not observed with citrate/UVB. Western blot analysis demonstrated that citrate/UVB led to phosphorylation of the stress signaling proteins, such as c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Furthermore, citrate/UVB caused activation of caspase-9/-3 as well as cleavage of poly(ADP-ribose) polymerase (PARP). Correspondingly, cell cycle analysis showed that citrate/UVB clearly increased the sub-G0/G1 phase, which indicated apoptotic cell death of B16 cells. Therefore, our study has demonstrated that sub-lethal doses of citrate enhanced the apoptotic cell death of melanoma cells under UVB irradiation. From these results, we suggest that citrate might reduce the risk of developing melanoma induced by UVB.

Phosphorylation of PTEN and Akt in astrocytes of the rat hippocampus following transient forebrain ischemia.

To ascertain whether the PTEN (phosphatase and tensin homolog deleted on chromosome 10)/Akt signaling pathway is activated during ischemic brain injury, we investigated the expression and phosphorylation of PTEN and Akt by immunohistochemistry in the rat hippocampus after transient forebrain ischemia. Weak immunoreactivity for PTEN and its phosphorylated form (p-PTEN) was constitutively expressed in hippocampal neurons and astrocytes of the control rats, but their upregulation was detected mainly in reactive astrocytes in the ischemic hippocampus. Increased immunoreactivity for PTEN and p-PTEN occurred specifically in astrocytes by day 1 and was sustained for more than 2 weeks. The spatiotemporal activation of Akt in the ischemic hippocampus mirrored that of p-PTEN expression. Post-ischemic activation of Akt, revealed by phosphorylated Akt (p-Akt) immunoreactivity, was first detected at day 1 and was maintained for at least 2 weeks. Double-labeling experiments revealed that the cells expressing PTEN, p-PTEN, or p-Akt were reactive astrocytes expressing glial fibrillary acidic protein. These results demonstrate the increased phosphorylation of PTEN and Akt in reactive astrocytes of the post-ischemic hippocampus, suggesting that the PTEN/Akt pathway is involved in the astroglial reaction in the rat hippocampus after transient forebrain ischemia.