Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma.

Osteolytic bone lesion is a major cause of lower quality of life and poor prognosis in patients with multiple myeloma (MM), but molecular pathogenesis of the osteolytic process in MM remains elusive. Fms-like tyrosine kinase 3 ligand (FLT3L) was reported to be elevated in bone marrow (BM) and blood of patients with advanced MM who often show osteolysis. Here, we investigated a functional link of FLT3L to osteolytic process in MM. We recruited 86, 306, and 52 patients with MM, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL), respectively. FLT3L levels of patients with hematologic malignancies were measured in BM-derived plasma and found to be significantly higher in MM than in AML or ALL, which rarely show osteolysis. FLT3L levels were further elevated in MM patients with bone lesion compared with patients without bone lesion. In vitro cell-based assays showed that the administration of FLT3L to HEK293T, HeLa, and U2OS cells led to an increase in the DKK1 transcript level through STAT3 phosphorylation at tyrosine 705. WNT reporter assay showed that FLT3L treatment reduced WNT signaling and nuclear translocation of ß-catenin. These results collectively show that the FLT3L-STAT3-DKK1 pathway inhibits WNT signaling-mediated bone formation in MM, which can cause osteolytic bone lesion. Finally, transcriptomic profiles revealed that FLT3L and DKK1 were predominantly elevated in the hyperdiploidy subtype of MM. Taken together, FLT3L can serve as a promising biomarker for predicting osteolytic bone lesion and also a potential therapeutic target to prohibit the progression of the osteolytic process in MM with hyperdiploidy.

The effects of the administration sequence and the type of hypnotics on the development of remifentanil-induced chest wall rigidity: a randomized controlled trial.

BACKGROUND: Research on remifentanil-induced chest wall rigidity is limited. Furthermore, its incidence is unknown, and the clinical factors influencing its development remain unclear. This prospective, double-blind, randomized controlled trial aimed to investigate the effects of the administration sequence of hypnotics and remifentanil as well as the type of hypnotic administered on the development of remifentanil-induced chest wall rigidity. METHODS: A total of 125 older patients aged [Formula: see text] 65 years, who were scheduled to undergo elective surgery under general anesthesia, were enrolled in this study. Participants were randomly assigned to one of four groups; Thio-Remi, Pro-Remi, Remi-Thio, or Remi-Pro. After confirming the loss of consciousness and achieving a target effect-site concentration of 3 ng/mL remifentanil, the development of remifentanil-induced chest wall rigidity was evaluated. RESULTS: The incidence of chest wall rigidity was significantly higher in the remifentanil-hypnotic group than in the hypnotic-remifentanil (opposite sequence) group (55.0% vs. 21.7%, P < 0.001). Logistic regression analysis revealed that remifentanil-hypnotic administration was a significant predictor of the development of chest wall rigidity (crude odds ratio 4.42, 95% confidence interval 1.99; 9.81, P < 0.001). CONCLUSIONS: Pretreatment with hypnotics potentially reduces the development of chest wall rigidity during the induction of balanced anesthesia with remifentanil in older patients. TRIAL REGISTRATION: This article was registered at WHO International Clinical Trials Registry Platform (Trial number: KCT0006542).

Casein Kinase 2 Alpha Inhibition Protects against Sepsis-Induced Acute Kidney Injury.

Sepsis-induced acute kidney injury (AKI) is a common complication in critically ill patients, often resulting in high rates of morbidity and mortality. Previous studies have demonstrated the effectiveness of casein kinase 2 alpha (CK2α) inhibition in ameliorating ischemia-reperfusion-induced AKI. In this study, our aim was to investigate the potential of the selective CK2α inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBBt), in the context of sepsis-induced AKI. To assess this, we initially confirmed an upregulation of CK2α expression following a cecum ligation and puncture (CLP) procedure in mice. Subsequently, TBBt was administered to a group of mice prior to CLP, and their outcomes were compared to those of sham mice. The results revealed that, following CLP, the mice exhibited typical sepsis-associated patterns of AKI, characterized by reduced renal function (evidenced by elevated blood urea nitrogen and creatinine levels), renal damage, and inflammation (indicated by increased tubular injury score, pro-inflammatory cytokine levels, and apoptosis index). However, mice treated with TBBt demonstrated fewer of these changes, and their renal function and architecture remained comparable to that of the sham mice. The anti-inflammatory and anti-apoptotic properties of TBBt are believed to be associated with the inactivation of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways. In conclusion, these findings suggest that inhibiting CK2α could be a promising therapeutic strategy for treating sepsis-induced AKI.

Conversion of Racemic Unnatural Amino Acids to Optically Pure Forms by a Coupled Enzymatic Reaction.

Genetic code expansion (GCE) technology is a useful tool for the site-specific modification of proteins. An unnatural amino acid (UAA) is one of the essential components of this technique, typically required at high concentration (1 mM or higher) in growth medium. The supply of UAAs is an important limitation to the application of GCE technology, as many UAAs are either expansive or commercially unavailable. In this study, two UAAs in a racemic mixture were converted into optically pure forms using two enzymes, the d-amino acid oxidase (RgDAAO) from Rhodotorula gracilis and the aminotransferase (TtAT) from Thermus thermophilus. In the coupled enzyme system, RgDAAO oxidizes the d-form of UAAs in a stereospecific manner and produces the corresponding α-keto acids, which are then converted into the l-form of UAAs by TtAT, resulting in the quantitative and stereospecific conversion of racemic UAAs to optically pure forms. The genetic incorporation of the optically pure UAAs into a target protein produced a better protein yield than the same experiments using the racemic mixtures of the UAAs. This method could not only be used for the preparation of optically pure UAAs from racemic mixtures, but also the broad substrate specificity of both enzymes would allow for its expansion to structurally diverse UAAs.

Truncation of MYH8 tail in AML: a novel prognostic marker with increase cell migration and epithelial-mesenchymal transition utilizing RAF/MAPK pathway.

MYH8 is an actin-based motor protin involved in integrin-mediated cell adhesion and migration. Heretofore, the association of MYH8 mutation and cancer is unclear. In this study, we investigated the biologic significance of novel MYH8 tail truncation mutation, R1292X, in acute myeloid leukemia (AML) which was discovered by whole-exome sequencing and targeted re-sequencing of 209 AML patients. The patients harboring the mutation all relapsed within 3.8-20.9 months. To explore the functional consequence of the mutation in AML progress, we established knock-in cell lines using CRISPR-Cas9 genome editing. Using the established mutant model, we assessed traits of cancer progress. The mutant cells had improved motility, which was confirmed by immunofluorescence staining, wound healing, transwell migration and adhesion assay. The cell morphology and cell cycle were altered to be accessible to migration and epithelial-to-mesenchymal transition (EMT) transcription factors were also increased. The Raf and p44/42 MAPK pathway was a major regulator of these characteristics proved by a screening of signal transduction and inhibitor assay. Further, a public cancer genome database (cBioPortal) shows that MYH8 tail truncation mutations occurring near the R1292 position of the genome may have a significant function in cancer. In conclusion, truncation of MYH8 could be a novel prognostic marker related to poor prognosis by inducing cell migration and EMT features, and inhibition of the Raf/MAPK pathway would be a therapeutic strategy for AML patients with MYH8 tail truncation.

Decreased vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration.

BACKGROUND: Vitamin C suppresses leukaemogenesis by modulating Tet methylcytosine dioxygenase (TET) activity. However, its beneficial effect in the treatment of patients with acute myeloid leukaemia (AML) remains controversial. In this study, we aimed to identify a potential predictive biomarker for vitamin C treatment in AML. METHODS: Gene expression patterns and their relevance to the survival of AML patients were analysed with The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database cases. In vitro experiments were performed on AML cell lines, a SLC2A3-knockdown cell line and patient-derived primary AML cells. RESULTS: SLC2A3 expression was significantly decreased in leukaemic blast cells. Below-median SLC2A3 expression was associated with poor overall survival. Low SLC2A3 expression was associated with less effective demethylation, and a diminished vitamin C effect in the AML and lymphoma cell lines. SLC2A3 knockdown in the KG-1 cell line decreased the response of vitamin C. In patient-derived primary AML cells, vitamin C only restored TET2 activity when SLC2A3 was expressed. CONCLUSION: SLC2A3 could be used as a potential biomarker to predict the effect of vitamin C treatment in AML.

Unsupervised learning of a deep neural network for metal artifact correction using dual-polarity readout gradients.

PURPOSE: A new unsupervised learning method was developed to correct metal artifacts in MRI using 2 distorted images obtained with dual-polarity readout gradients. METHODS: An unsupervised learning method is proposed for a deep neural network architecture consisting of a deep neural network and an MR image generation module. The architecture is trained as an end-to-end process without the use of distortion-free images or off-resonance frequency maps. The deep neural network estimates frequency-shift maps between 2 distorted images that are obtained using dual-polarity readout gradients. From the estimated frequency-shift maps and 2 distorted input images, distortion-corrected images are obtained with the MR image generation module. Experiments using synthetic data and actual MR data were performed to compare images corrected by several metal-artifact-correction methods. RESULTS: The proposed method resolved the ripple and pile-up artifacts in the reconstructed images from synthetic data and actual MR data. The results from the proposed method were comparable to those from supervised-learning methods and superior to the compared model-based method. The proposed unsupervised learning method enabled the network to be trained without labels and to be more robust than supervised learning methods, for which overfitting problems can arise when using small training data sets. CONCLUSION: Metal artifacts in the MR image were drastically corrected by the proposed unsupervised learning method. Two distorted images obtained with dual-polarity readout gradients are used as the input of the deep neural network. The proposed method can train networks without labels and does not overfit the network, even with small training data sets.

Non-contrast-enhanced peripheral MR angiography using velocity-selective excitation.

PURPOSE: To develop a new non-contrast-enhanced peripheral MR angiography that provides a high contrast angiogram without using electrocardiography triggering and saturation radiofrequency pulses. METHODS: A velocity-selective excitation technique is used in conjunction with the golden-angle radial sampling scheme. The signal amplitude varies according to the velocity of the flow by the velocity-selective excitation technique. Because the arterial blood velocity varies depending on the cardiac phase, the acquired data can be classified into systolic and diastolic phase based on the signal amplitude of the artery. Two images are then reconstructed from the systolic and diastolic phase data, respectively, and an image reflecting the differences between the two images is obtained to eliminate background and vein signals. The performance of the proposed method was compared with the quiescent-interval single shot (QISS) in eight healthy subjects and an elderly subject. RESULTS: The proposed method generated fewer residual venous and background signals than the QISS. Furthermore, the maximum intensity projection images, the relative contrast, and the apparent contrast-to-noise ratio results showed that the proposed method produced a better contrast than the QISS. CONCLUSIONS: The proposed non-contrast-enhanced peripheral MR angiography technique can provide a high contrast angiogram without the use of electrocardiography triggering and saturation radiofrequency pulses. Magn Reson Med 79:779-788, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Retrospective motion gating in cardiac MRI using a simultaneously acquired navigator.

A simultaneous acquisition technique of image and navigator signals (simultaneously acquired navigator, SIMNAV) is proposed for cardiac magnetic resonance imaging (CMRI) in Cartesian coordinates. To simultaneously acquire both image and navigator signals, a conventional balanced steady-state free precession (bSSFP) pulse sequence is modified by adding a radiofrequency (RF) pulse, which excites a supplementary slice for the navigator signal. Alternating phases of the RF pulses make it easy to separate the simultaneously acquired magnetic resonance data into image and navigator signals. The navigator signals of the proposed SIMNAV were compared with those of current gating devices and self-gating techniques for seven healthy subjects. In vivo experiments demonstrated that SIMNAV could provide cardiac cine images with sufficient image quality, similar to those from electrocardiogram (ECG) gating with breath-hold. SIMNAV can be used to acquire a cardiac cine image without requiring an ECG device and breath-hold, whilst maintaining feasible imaging time efficiency.

Self-gated cardiac cine imaging using phase information.

PURPOSE: To obtain multiphase cardiac cine images with high resolution, a novel self-gating method for both cardiac and respiratory motions is proposed. METHODS: The proposed method uses the phase of projection data obtained from a separate axial slice to measure cardiac and respiratory motion, after the acquisition of every k-space line in the image plane. Cardiac motion is estimated from the phase of the projection data passing through the aorta, which is amplified by superior-inferior directional bipolar gradients, whereas respiratory motion is estimated from the phase of the left-right directional projection data of the abdomen. To verify the proposed self-gating method, a simulation and in vivo steady state free precession cardiac imaging were performed. RESULTS: The proposed method provides high resolution multiphase cardiac cine images. Using the proposed self-gating method, the phase variation of the projection data offers information about cardiac and respiratory motions that is equivalent to external gating devices. CONCLUSION: The proposed method can capture time-resolved cardiac and respiratory motion from the phase information of the projection data. Because the projection data is obtained from a separate gating slice, the self-gating signals are not affected by imaging planes. Magn Reson Med 77:1216-1222, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Efficient hardware implementation of the lightweight block encryption algorithm LEA.

Recently, due to the advent of resource-constrained trends, such as smartphones and smart devices, the computing environment is changing. Because our daily life is deeply intertwined with ubiquitous networks, the importance of security is growing. A lightweight encryption algorithm is essential for secure communication between these kinds of resource-constrained devices, and many researchers have been investigating this field. Recently, a lightweight block cipher called LEA was proposed. LEA was originally targeted for efficient implementation on microprocessors, as it is fast when implemented in software and furthermore, it has a small memory footprint. To reflect on recent technology, all required calculations utilize 32-bit wide operations. In addition, the algorithm is comprised of not complex S-Box-like structures but simple Addition, Rotation, and XOR operations. To the best of our knowledge, this paper is the first report on a comprehensive hardware implementation of LEA. We present various hardware structures and their implementation results according to key sizes. Even though LEA was originally targeted at software efficiency, it also shows high efficiency when implemented as hardware.

Pursuing dynamics of minimal residual leukemic subclones in relapsed and refractory acute myeloid leukemia during conventional therapy.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by clonal heterogeneity, leading to frequent relapses and drug resistance despite intensive clinical therapy. Although AML's clonal architecture has been addressed in many studies, practical monitoring of dynamic changes in those subclones during relapse and treatment is still understudied. METHOD: Fifteen longitudinal bone marrow (BM) samples were collected from three relapsed and refractory (R/R) AML patients. Using droplet digital polymerase chain reaction (ddPCR), the frequencies of patient's leukemic variants were assessed in seven cell populations that were isolated from each BM sample based on cellular phenotypes. By quantifying mutant clones at the diagnosis, remission, and relapse stages, the distribution of AML subclones was sequentially monitored. RESULTS: Minimal residual (MR) leukemic subclones exhibit heterogeneous distribution among BM cell populations, including mature leukocyte populations. During AML progression, these subclones undergo active phenotypic transitions and repopulate into distinct cell population regardless of normal hematopoiesis hierarchic order. Of these, MR subclones in progenitor populations of patient BM predominantly carry MR leukemic properties, leading to more robust expansion and stubborn persistence than those in mature populations. Moreover, a minor subset of MR leukemic subclones could be sustained at an extremely low frequency without clonal expansion during relapse. CONCLUSIONS: In this study, we observed treatment persistent MR leukemic subclones and their phenotypic changes during the treatment process of R/R AML patients. This underscores the importance of preemptive inhibition of clonal promiscuity in R/R AML, proposing a practical method for monitoring AML MR subclones.

Analysis of risk factors for disease progression after salvage radiation therapy with androgen deprivation therapy in prostate cancer patients who have prostate-specific antigen persistence after radical prostatectomy.

PURPOSE: To assess risk factors of disease progression after salvage radiation therapy (SRT) with androgen deprivation therapy (ADT) in case of prostate-specific antigen (PSA) persistence after radical prostatectomy (RP). MATERIALS AND METHODS: We analyzed 57 patients who received SRT with ADT between 2013 and 2019 due to PSA persistence after RP. The endpoint was disease progression defined by biochemical recurrence or clinical recurrence. Age, Pre-RP PSA level, Gleason score, pathologic stage, presence of pelvic lymph node dissection, surgical margins, and PSA at 6-8 weeks after RP were analyzed as predictive factors for disease progression. Kaplan-Meier method and Cox regression models were used for data analysis. RESULTS: At a median follow-up of 38 months (interquartile range, 26-61), 17 patients had disease progression. Pathologic T stage (pT3b vs. pT3a or lower; hazard ratio [HR] = 9.20; p = 0.035) and PSA level at 6-8 weeks after RP (≥2.04 vs. <2.04 ng/mL; HR = 5.85; p = 0.002) were predictors of disease progression. The 5-year disease progression-free survival rate was 46.7% in pT3b group as compared to 92.9 % in pT3a or lower group, and 18.4% for PSA ≥2.04 ng/mL after RP as compared to 79.2% for PSA <2.04 ng/mL. CONCLUSION: Pathological T stage (pT3b) and post RP PSA ≥2.04 ng/mL are independent risk factors of disease progression after SRT with ADT in patients with PSA persistence after RP.

Targeting of CYP2E1 by miRNAs in alcohol-induced intestine injury.

Although binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species-mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as well. Ethanol (EtOH)-inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in EtOH metabolism, promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by mediating changes in intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that EtOH promotes CYP2E1 induction and activation, the mechanisms that regulate CYP2E1 expression in the context of intestinal damage remain poorly defined. Specific miRNAs, including miR-132, miR-212, miR-378, and miR-552, have been shown to repress the expression of CYP2E1, suggesting that these miRNAs contribute to EtOH-induced intestinal injury. Here, we have shown that CYP2E1 expression is regulated post-transcriptionally through miRNA-mediated degradation, as follows: (1) the RNA-binding protein AU-binding factor 1 (AUF1) binds mature miRNAs, including CYP2E1-targeting miRNAs, and this binding modulates the degradation of corresponding target mRNAs upon EtOH treatment; (2) the serine/threonine kinase mammalian Ste20-like kinase 1 (MST1) mediates oxidative stress-induced phosphorylation of AUF1. Those findings suggest that reactive oxygen species-mediated signaling modulates AUF1/miRNA interaction through MST1-mediated phosphorylation. Thus, our study demonstrates the critical functions of AUF1 phosphorylation by MST1 in the decay of miRNAs targeting CYP2E1, the stabilization of CYP2E1 mRNA in the presence of EtOH, and the relationship of this pathway to subsequent intestinal injury.

Prognostic circulating proteomic biomarkers in colorectal liver metastases.

The liver is the most common site of metastasis in colorectal cancer. Multimodal treatment, including liver resection, is potentially curative and prolongs survival for selected patients with colorectal liver metastases (CRLM). However, the treatment of CRLM remains challenging because recurrence is common, and prognosis varies widely between patients despite curative-intent treatment. Clinicopathological features and tissue-based molecular biomarkers, either alone or in combination, are insufficient for accurate prognostication. As most of the functional information in cells resides in the proteome, circulating proteomic biomarkers may be useful for rationalising the molecular complexities of CRLM and identifying potentially prognostic molecular subtypes. High-throughput proteomics has accelerated a range of applications including protein profiling of liquid biopsies for biomarker discovery. Moreover, these proteomic biomarkers may provide non-invasive prognostic information even before CRLM resection. This review evaluates recently discovered circulating proteomic biomarkers in CRLM. We also highlight some of the challenges and opportunities with translating these discoveries into clinical applications.

Rapid MRI Abdomen for Assessment of Clinically Suspected Acute Appendicitis in the General Adult Population: a Systematic Review.

OBJECTIVES: To perform a systematic review on the use of magnetic resonance imaging (MRI) of the abdomen to evaluate clinically suspected appendicitis in the general adult population. We examined the diagnostic accuracy, the reported trends of MRI use, and the factors that affect the utility of MRI abdomen, including study duration and cost-benefits. METHODS: We conducted a systematic literature search on PubMed, MEDLINE, Embase, Web of Science, and Cochrane Library databases. We enrolled primary studies investigating the use of MRI in diagnosing appendicitis in the general adult population, excluding studies that predominantly reported on populations not representative of typical adult appendicitis presentations, such as those focusing on paediatric or pregnant populations. RESULTS: Twenty-seven eligible primary studies and 6 secondary studies were included, totaling 2,044 patients from eight countries. The sensitivity and specificity of MRI for diagnosing appendicitis were 96% (95% CI: 93-97%) and 93% (95% CI: 80-98%), respectively. MRI can identify complicated appendicitis and accurately propose alternative diagnoses. The duration of MRI protocols in each primary study ranged between 2.26 and 30 minutes, and only one study used intravenous contrast agents in addition to the non-contrast sequences. Decision analysis suggests significant benefits for replacing computed tomography (CT) with MRI and a potential for cost reduction. Reported trends in MRI usage showed minimal utilisation in diagnostic settings even when MRI was available. CONCLUSIONS: MRI accurately diagnoses appendicitis in the general adult population and improves the identification of complicated appendicitis or alternative diagnoses compared to other modalities using a single, rapid investigation.

Interfacial Bond Properties of Underwater Concrete Coated with Bisphenol A Epoxy Resins.

This study investigated changes in the interfacial properties of epoxy-coated concrete exposed to various conditions, regarding the epoxy type, coating equipment, and exposure environment and period. The measured coating thickness and pull-off bond strength exhibited diverse trends, depending on the exposure period and conditions. In the real sea (RS) environment, the average bond strengths for bisphenol A (BPA) (E1), BPA with zinc powder (E2), and BPA with cresyl glycidyl ether (E3) were 1.26, 1.93, and 1.92 MPa, respectively. The coating method did not significantly affect the measured coating thickness and strength values. The conventional roller (D1) exhibited the highest thickness variation, with a value of 214.45 µm. The RS condition significantly increased the coating thickness (34% to 158%) compared to the tap water (TW) condition. The exposure conditions had little impact on bond strength except for E3, which showed an increased strength (2.71 MPa) over 7-91 days, especially under RS conditions, while E2 remained constant at approximately 1.82 MPa. This study offers insights into factors influencing marine concrete coating performance and discusses limitations and future work.

Appropriateness of the anxiety subscale of the Hospital Anxiety and Depression Scale for Koreans to measure preoperative anxiety and the effect of preoperative anxiety on postoperative quality of recovery.

BACKGROUND: The reliability and validity of the anxiety subscale of the Hospital Anxiety and Depression Scale for Koreans (K-HADS-A) has not been studied in Korean surgical patients. This study aimed to validate the usefulness of K-HADS-A for measuring preoperative anxiety in Korean surgical patients. Additionally, the effect of preoperative anxiety on postoperative quality of recovery was evaluated. METHODS: Preoperative anxiety in 126 inpatients with planned elective surgery was measured using the K-HADS-A. The postoperative quality of recovery was measured using the Korean version of the Quality of Recovery-15. The validity and reliability of the K-HADS-A were evaluated. The differences in quality of recovery on the first and seventh day postoperatively were then compared between the anxious and non-anxious groups. RESULTS: There was a statistical correlation between the K-HADS-A and Anxiety Likert Scale. The goodness-of-fit indices of the structural equation model showed how well the data from the K-HADS-A match their concept. The Kaiser-Meyer-Olkin value was 0.848, and the P value of Bartlett's test of sphericity was < 0.001. Cronbach's alpha was high at 0.872. The K-HADS-A had an acceptable level of validity and reliability. Postoperative quality of recovery was significantly lower in the anxious group (postoperative day 1: t = 2.058, P = 0.042; postoperative day 7: t = 3.430, P = 0.002). CONCLUSIONS: The K-HADS-A is an acceptable tool for appropriately assessing preoperative anxiety in Korean surgical patients. Assessing preoperative anxiety is valuable, because preoperative anxiety affects the postoperative quality of mental and physical recovery.