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Multiple myeloma (MM) frequently acquires multidrug resistance (MDR), which is due to poor prognosis. Our previous study indicated that high expression of Survivin and multidrug resistance protein 1 (MDR1) and decreased expression of Bim are associated with MDR in adriamycin- and dexamethasone-resistant cells. However, the fundamental mechanism of MDR in adriamycin- and dexamethasone-resistant MM cells is still unidentified. In this study, we examined the MDR mechanism in adriamycin- and dexamethasone-resistant cells. RPMI8226/ADM, ARH-77/ADM, RPMI8226/DEX, and ARH-77/DEX cells exhibited enhanced nuclear factor κB (NF-κB) p65, Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Combination treatment with NF-κB p65, phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase 1/2 (MEK1/2) inhibitors resensitized to adriamycin and dexamethasone via increased Bim expression. Although treatment with MDR1 or Survivin siRNA did not overcome adriamycin and dexamethasone resistance in RPMI8226/ADM and RPMI8226/DEX cells, administration of Bim siRNA induced adriamycin and dexamethasone resistance in RPMI8226 cells. Moreover, low expression of Bim was related to poor prognosis in MM patients. These results indicate that activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance via decreasing Bim expression, and these signal inhibitor combinations overcome drug resistance in MM. These findings suggest that combination treatment with these inhibitors and adriamycin or dexamethasone may be a promising therapy for adriamycin- and dexamethasone-resistant MM., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

We study the electronic structure of the ferromagnetic spinel HgCr_{2}Se_{4} by soft-x-ray angle-resolved photoemission spectroscopy (SX-ARPES) and first-principles calculations. While a theoretical study has predicted that this material is a magnetic Weyl semimetal, SX-ARPES measurements give direct evidence for a semiconducting state in the ferromagnetic phase. Band calculations based on the density functional theory with hybrid functionals reproduce the experimentally determined band gap value, and the calculated band dispersion matches well with ARPES experiments. We conclude that the theoretical prediction of a Weyl semimetal state in HgCr_{2}Se_{4} underestimates the band gap, and this material is a ferromagnetic semiconductor.

Objectives: We evaluated the feasibility of using deep learning with a convolutional neural network for predicting bone mineral density (BMD) and bone microarchitecture from conventional computed tomography (CT) images acquired by multivendor scanners., Methods: We enrolled 402 patients who underwent noncontrast CT examinations, including L1-L4 vertebrae, and dual-energy x-ray absorptiometry (DXA) examination. Among these, 280 patients (3360 sagittal vertebral images), 70 patients (280 sagittal vertebral images), and 52 patients (208 sagittal vertebral images) were assigned to the training data set for deep learning model development, the validation, and the test data set, respectively. Bone mineral density and the trabecular bone score (TBS), an index of bone microarchitecture, were assessed by DXA. BMDDL and TBSDL were predicted by deep learning with a convolutional neural network (ResNet50). Pearson correlation tests assessed the correlation between BMDDL and BMD, and TBSDL and TBS. The diagnostic performance of BMDDL for osteopenia/osteoporosis and that of TBSDL for bone microarchitecture impairment were evaluated using receiver operating characteristic curve analysis., Results: BMDDL and BMD correlated strongly (r = 0.81, P < 0.01), whereas TBSDL and TBS correlated moderately (r = 0.54, P < 0.01). The sensitivity and specificity of BMDDL for identifying osteopenia or osteoporosis were 93% and 90%, and 100% and 94%, respectively. The sensitivity and specificity of TBSDL for identifying patients with bone microarchitecture impairment were 73% for all values., Conclusions: The BMDDL and TBSDL derived from conventional CT images could identify patients who should undergo DXA, which could be a gatekeeper tool for detecting latent osteoporosis/osteopenia or bone microarchitecture impairment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Excessive immunosuppression after kidney transplantation (KT) is often encountered in patients undergoing therapy for anti-rejection or autoimmune disease that requires further treatment using immunosuppressive medications (IMs), including biologic agents. We report a novel case wherein a kidney transplant recipient developed severe acute allograft injury and hemorrhagic cystitis at 4.5 years after KT due to adenovirus nephritis after treatment with infliximab for Crohn's disease. The diagnosis was made based on adenovirus immunohistochemistry staining and urine polymerase chain reaction tests. The patient was successfully treated by reducing IMs and administration of immunoglobulin even though allograft function was eventually partially recovered. When new immunosuppressive agents, particularly biologic agents, are initiated for other diseases in addition to maintenance IMs, the following points need to be regarded: (1) pay attention to opportunistic infections even in the late phase of KT, and (2) maintain communication with other specialists who prescribe biologics to ensure appropriate administration of IMs., (© 2022. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

We investigate ultrafast dynamics of the anomalous Hall effect (AHE) in the topological antiferromagnet Mn&#95;{3}Sn with sub-100 fs time resolution. Optical pulse excitations largely elevate the electron temperature up to 700 K, and terahertz probe pulses clearly resolve ultrafast suppression of the AHE before demagnetization. The result is well reproduced by microscopic calculation of the intrinsic Berry-curvature mechanism while the extrinsic contribution is clearly excluded. Our work opens a new avenue for the study of nonequilibrium AHE to identify the microscopic origin by drastic control of the electron temperature by light.

The rph gene cluster for prodigiosin biosynthesis has been identified in Streptomyces griseoviridis 2464-S5, which produces cyclic prodigiosin derivatives including roseophilin (2), prodigiosin R1 (3) and prodigiosin R2 (4). A new cyclic prodigiosin, prodigiosin R3 (1), was produced by the redG redP double disruptant of Streptomyces coelicolor M511 expressing four cyclization gene candidates (rphG, rphG2, rphG3 and rphG4) in the rph cluster. The same compound was isolated from Streptomyces griseoviridis 2464-S5. The molecular formula of 1 was established as C 27 H 33 N 3 O by ESI and FAB mass spectrometry. The structure was determined to be a multicyclic prodigiosin with three alkyl linkages by NMR spectroscopic analysis. Prodigiosin R3 (1) showed cytotoxicity against HeLa human cervical carcinoma cells and HT1080 human fibrosarcoma cells with IC 50 s of 2.1 µM and 3.2 µM, respectively., (© 2022. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Using broadband (12-45 THz) multi-terahertz spectroscopy, we show that stimulated Rayleigh scattering dominates the transient optical conductivity of cadmium arsenide, a Dirac semimetal, under an optical driving field at 30 THz. The characteristic dispersive line shape with net optical gain is accounted for by optical transitions between light-induced Floquet subbands, strikingly enhanced by the longitudinal plasma mode. Stimulated Rayleigh scattering with an unprecedentedly large refractive index change may pave the way for slow light generation in conductive solids at room temperature.

Objectives: Serial pancreatic juice aspiration cytological examination (SPACE) via endoscopic retrograde cholangiopancreatography is a useful diagnostic method for early-stage pancreatic cancer, such as carcinoma in situ that are difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, the diagnostic accuracy of SPACE is low, which is attributed to problems regarding specimen treatment. Hence, we evaluated the diagnostic efficacy of liquid-based cytology (LBC) in pancreatic juice cytology for pancreatic cancer., Methods: We retrospectively analyzed 24 patients with suspected pancreatic cancer that was difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration who underwent SPACE using LBC between April 2017 and April 2021., Results: The most common reason for performing SPACE was localized stenosis of the main pancreatic duct without a mass. Eleven patients were diagnosed with malignancy after surgical resection, nine of whom had pancreatic ductal adenocarcinoma. Ten patients were diagnosed as benign after a follow-up of more than 1 year. The nine cases of malignancy were diagnosed before surgical resection by SPACE using LBC, with a sensitivity of 81.8% and specificity of 100%. The overall diagnostic accuracy was 91.7%. A total of 152 LBC examinations were performed via SPACE, with an adequate sample collection rate of 88.9%. No adverse events, including acute pancreatitis, occurred after endoscopic retrograde cholangiopancreatography., Conclusion: SPACE with LBC offers good diagnostic efficacy in patients with pancreatic cancer that is difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Tamoxifen resistance remains a major obstacle in the treatment of estrogen receptor (ER)‑positive breast cancer. In recent years, the crucial role of the epithelial‑mesenchymal transition (EMT) process in the development of drug resistance in breast cancer has been underlined. However, the central molecules inducing the EMT process during the development of tamoxifen resistance remain to be elucidated. In the present study, it was demonstrated that tamoxifen‑resistant breast cancer cells underwent EMT and exhibited an enhanced cell motility and invasive behavior. The inhibition of snail family transcriptional repressor 1 ( Snail ) and twist family BHLH transcription factor 1 ( Twist ) reversed the EMT phenotype and decreased the tamoxifen resistance, migration and invasion of tamoxifen‑resistant breast cancer cells. In addition, it was observed that the inhibition of epidermal growth factor receptor (EGFR) reversed the EMT phenotype in tamoxifen‑resistant MCF7 (MCF‑7/TR) cells via the downregulation of Snail and Twist . Notably, the EGFR inhibitor, gefitinib, decreased tamoxifen resistance, migration and invasion through the inhibition of Snail and Twist . On the whole, the results of the present study suggest that EGFR may be a promising therapeutic target for tamoxifen‑resistant breast cancer. Moreover, it was suggested that gefitinib may serve as a potent novel therapeutic strategy for breast cancer patients, who have developed tamoxifen resistance.

The electromagnetic response of Dirac semimetals in the infrared and terahertz frequency ranges is attracting growing interest for potential applications in optoelectronics and nonlinear optics. The interplay between the free-carrier response and interband transitions in the gapless, linear dispersion relation plays a key role in enabling novel functionalities. Here we investigate ultrafast dynamics in thin films of a photoexcited Dirac semimetal Cd 3 As 2 by probing the broadband response functions as complex quantities in the multiterahertz region (10-45 THz, 40-180 meV, or 7-30 μm), which covers the crossover between the inter- and intraband response. We resolve dynamics of the photoexcited nonthermal electrons, which merge with originally existing carriers to form a single thermalized electron gas and how it is facilitated by high-density excitation. We also demonstrate that a large reduction of the refractive index by 80% dominates the nonequilibrium infrared response, which can be utilized for designing ultrafast switches in active optoelectronics.

Background/aim: Sarcopenia increases the mortality in patients with cirrhosis. Approximately 60% of zinc is accumulated in skeletal muscle. We aimed to determine the role of subclinical zinc deficiency on sarcopenia development in patients with cirrhosis., Patients and Methods: We enrolled 151 patients with cirrhosis and divided them into the group with normal serum zinc levels (Group N: 80-130 μg/dl; n=38) and group with subclinical zinc deficiency (Group D: <80 μg/dl; n=113). The risk factors for sarcopenia were then investigated., Results: Group D had more sarcopenia cases than Group N (31.0% vs. 13.2%). In group D, HGS exhibited a weakly positive but significant correlation with serum zinc levels (R=0.287, p=0.00212), serum zinc levels negatively correlated with both ammonia and myostatin levels (R=-0.254, p=0.0078; R=-0.33, p<0.01), and low zinc levels were independently associated with sarcopenia development., Conclusion: Patients with cirrhosis showing subclinical zinc deficiency have a significantly higher risk of developing sarcopenia., Competing Interests: The Authors declare no conflicts of interest., (Copyright 2022, International Institute of Anticancer Research.)

Background: The prevalence of overweight and obesity has increased, not just in adults but also in children. In Japan, the percentage of overweight (POW) is widely used for the estimation and assessment of percentage body fat (PBF) for children. We examine whether there is a difference between normal height and short stature children in terms of the relationship between POW and PBF., Methods: A total of 321 children of normal height (163 boys, 158 girls) and 106 children with short stature (78 boys, 28 girls) were assessed according to sex. Percentage of overweight was used to represent the degree of obesity. The PBF of the total body was examined by dual energy X-ray absorptiometry., Results: According to their PBF, normal height subjects of both sexes were classified as obese if they had a POW of more than 20%. However, short-stature subjects of both sexes were not classified as obese until the boys had a POW of 40%, and girls had a POW of 35%, respectively. Thus, overweight or obesity is overestimated in short stature children in both males and females with the rule "POW above 20% is recognized as obesity.", Conclusions: Percentage of overweight is commonly considered as a good surrogate measure for determining overweight and obesity in children of both sexes. However, this study has clarified that body fat accumulation is overestimated in children with short stature when using the POW measurement., (© 2021 Japan Pediatric Society.)

Objective: Albumin-globulin ratio (AGR), which is calculated by dividing serum albumin by serum globulin, is considered as a cancer-related inflammation biomarker. Although the prognosis of many solid cancers has been shown to be associated with AGR, there are no studies to demonstrate the association between the prognosis of thyroid cancer and AGR. The purpose of this study is to reveal the relationship between AGR and overall survival (OS) in patients with thyroid cancer who received radioactive iodine therapy (RIT)., Methods: Eighty-eight patients with thyroid cancer who had received RIT for the first time in our institution were included. The values before RIT were adopted as initial measurements for serum albumin, globulin, and thyroglobulin (Tg) and used for analysis. Patients were divided into two groups based on the AGR value. We analyzed the relationship between clinical factors and treatment outcome., Results: The median follow-up period was 92.4 months (range: 30.1-173.9 months). The 5-year OS and progression-free survival (PFS) were 94% and 54%, respectively. Seventeen patients (< 65 years, 8; and ≥ 65 years, 9) died during the follow-up period. Low AGR was significantly associated with OS in both univariate and multivariate analyses (p = 0.0059 and p = 0.0120, respectively). As the 5-year OS was as high as 94%, there was no significant difference in survival rate between the two groups during the first 5 years. However, there seemed to be a remarkable difference in 10 years after the first RIT. On the other hand, Tg was significantly associated with PFS in both univariate and multivariate analyses (p = 0.0016 and p = 0.0441, respectively). In patients under the age of 65, the PFS rate was significantly lower in the low AGR group (p < 0.0001), while there was no difference in PFS rate between the two AGR groups in patients aged 65 years or older., Conclusions: AGR may be used as a prognostic factor in relatively younger patients with thyroid cancer treated with radioiodine, while it may be less useful in the older. Overall, it may be an independent prognostic factor for long-term survival in those with thyroid cancer., (© 2021. The Japanese Society of Nuclear Medicine.)

We herein report a 52-year-old man with multiple hypoechoic lesions in the body and tail of the pancreas detected during a screening ultrasound. Computed tomography (CT) showed no lesions other than those in the pancreas and peripheral lymph nodes. Contrast-enhanced CT identified hypovascular tumors in the pancreas. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) demonstrated partial fibrosis and noncaseating granulomas with Langhans giant cells. To our knowledge, this is the first report of isolated pancreatic sarcoidosis diagnosed by EUS-FNA. Although pancreatic sarcoidosis is very rare, clinicians should be aware of this possibility in patients presenting with multiple hypovascular pancreatic tumors.

Myocardial ischemia is caused by a mismatch between myocardial oxygen consumption and oxygen delivery in coronary artery disease (CAD). Stratification and decision-making based on ischemia improves the prognosis in patients with CAD. Non-invasive tests used to evaluate myocardial ischemia include stress electrocardiography, echocardiography, single-photon emission computed tomography, and magnetic resonance imaging. Invasive fractional flow reserve is considered the reference standard for assessment of the hemodynamic significance of CAD. Computed tomography (CT) angiography has emerged as a first-line imaging modality for evaluation of CAD, particularly in the population at low to intermediate risk, because of its high negative predictive value; however, CT angiography does not provide information on the hemodynamic significance of stenosis, which lowers its specificity. Emerging techniques, e.g., CT perfusion and CT-fractional flow reserve, help to address this limitation of CT, by determining the hemodynamic significance of coronary artery stenosis. CT perfusion involves acquisition during the first pass of contrast medium through the myocardium following pharmacological stress. CT-fractional flow reserve uses computational fluid dynamics to model coronary flow, pressure, and resistance. In this article, we review these two functional CT techniques in the evaluation of myocardial ischemia, including their principles, technology, advantages, limitations, pitfalls, and the current evidence.

Pentatricopeptide repeat (PPR) proteins, composed of PPR motifs repeated in tandem, are sequence-specific RNA binding proteins. Recent bioinformatic studies have shown that the combination of polar amino acids at positions 5 and last in each PPR motif recognizes RNA bases, and an RNA recognition code for PPR proteins has been proposed. Subsequent studies confirmed that the P (canonical length) and S (short) motifs bind to specific nucleotides according to this code. However, the contribution of L (long) motifs to RNA recognition is mostly controversial, owing to the presence of a nonpolar amino acid at position 5. The PLS-class PPR protein PpPPR&#95;56 is a mitochondrial RNA editing factor in the moss Physcomitrella patens. Here, we performed in vitro RNA binding and in vivo complementation assays with PpPPR&#95;56 and its variants containing mutated L motifs to investigate their contributions to RNA recognition. In vitro RNA binding assay showed that the original combination of amino acids at positions 5 and last in the L motifs of PpPPR&#95;56 is not required for RNA recognition. In addition, an in vivo complementation assay with RNA editing factors PpPPR&#95;56 and PpPPR&#95;78 revealed the importance of nonpolar amino acids at position 5 of C-terminal L motifs for efficient RNA editing. Our findings suggest that L motifs function as non-binding spacers, not as RNA-binding motifs, to facilitate the formation of a complex between PLS-class PPR protein and RNA. As a result, the DYW domain, a putative catalytic deaminase responsible for C-to-U RNA editing, is correctly placed in proximity to C, which is to be edited., Competing Interests: The authors have declared that no competing interests exist.

We report strong terahertz (∼10^{12}  Hz) high harmonic generation at room temperature in thin films of Cd&#95;{3}As&#95;{2}, a three-dimensional Dirac semimetal. Third harmonics are detectable with a tabletop light source and can be as strong as 100  V/cm by applying a fundamental field of 6.5  kV/cm inside the film, demonstrating an unprecedented efficiency for terahertz frequency conversion. Our time-resolved terahertz spectroscopy and calculations also clarify the microscopic mechanism of the nonlinearity originating in the coherent acceleration of Dirac electrons in momentum space. Our results provide clear insights for nonlinear currents of Dirac electrons driven by the terahertz field under the influence of scattering, paving the way toward novel devices for high-speed electronics and photonics based on topological semimetals.

Antiferromagnetic spin motion at terahertz (THz) frequencies attracts growing interests for fast spintronics, however, their smaller responses to external field inhibit device application. Recently the noncollinear antiferromagnet Mn 3 Sn, a Weyl semimetal candidate, was reported to show large anomalous Hall effect (AHE) at room temperature comparable to ferromagnets. Dynamical aspect of such large responses is an important issue to be clarified for future THz data processing. Here the THz anomalous Hall conductivity in Mn 3 Sn thin films is investigated by polarization-resolved spectroscopy. Large anomalous Hall conductivity [Formula: see text] at THz frequencies is clearly observed as polarization rotation. A peculiar temperature dependence corresponding to the breaking/recovery of symmetry in the spin texture is also discussed. Observation of the THz AHE at room temperature demonstrates the ultrafast readout for the antiferromagnetic spintronics using Mn 3 Sn, and will also open new avenue for studying nonequilibrium dynamics in Weyl antiferromagnets.

Chloroplast gene expression is controlled by numerous nuclear-encoded RNA-binding proteins. Among these, pentatricopeptide repeat (PPR) proteins are known to be key players in post-transcriptional regulation in chloroplasts. However, the functions of many PPR proteins remain unknown. In this study, we characterized the function of a chloroplast-localized P-class PPR protein PpPPR&#95;21 in Physcomitrella patens. Knockout (KO) mutants of PpPPR&#95;21 exhibited reduced protonemata growth and lower photosynthetic activity. Immunoblot analysis and blue-native gel analysis showed a remarkable reduction of the photosystem II (PSII) reaction center protein and poor formation of the PSII supercomplexes in the KO mutants. To assess whether PpPPR&#95;21 is involved in chloroplast gene expression, chloroplast genome-wide microarray analysis and Northern blot hybridization were performed. These analyses indicated that the psbI-ycf12 transcript encoding the low molecular weight subunits of PSII did not accumulate in the KO mutants while other psb transcripts accumulated at similar levels in wild-type and KO mutants. A complemented PpPPR&#95;21KO moss transformed with the cognate full-length PpPPR&#95;21cDNA rescued the level of accumulation of psbI-ycf12 transcript. RNA-binding experiments showed that the recombinant PpPPR&#95;21 bound efficiently to the 5' untranslated and translated regions of psbImRNA. The present study suggests that PpPPR&#95;21 may be essential for the accumulation of a stable psbI-ycf12mRNA., (© 2018 The Authors The Plant Journal © 2018 John Wiley & Sons Ltd.)

Roseophilin (2) is a unique prodigiosin-related compound produced by Streptomyces griseoviridis 2464-S5, and is characterized by a central furan ring and a bicyclic alkyl chain. During a search for biosynthetic intermediates of 2, a new metabolite designated prodigiosin R2 (1) was isolated from the culture of the roseophilin producer. The molecular formula of 1 was established as C 27 H 35 N 3 O by high-resolution FAB-MS. The structure of 1 was determined by NMR spectroscopic analyses as a prodigiosin derivative with the same bicyclic alkyl chain as 2. Prodigiosin R2 (1) showed potent cytotoxicity against HeLa human cervical carcinoma cells and HT1080 human fibrosarcoma cells with IC 50 s of 0.41 and 0.82 μM, respectively.

We evaluated the image quality and diagnostic performance of late iodine enhancement (LIE) in dual-source computed tomography (DSCT) with low kilo-voltage peak (kVp) images and a denoise filter for the detection of acute myocardial infarction (AMI) in comparison with late gadolinium enhancement (LGE) magnetic resonance imaging (MRI). The Hospital Ethics Committee approved the study protocol. Before discharge, 19 patients who received percutaneous coronary intervention after AMI underwent DSCT and 1.5 T MRI. Immediately after coronary computed tomography (CT) angiography, contrast medium was administered at a slow injection rate. LIE-CT scans were acquired via dual-energy CT and reconstructed as 100-, 140-kVp, and mixed images. An iterative three-dimensional edge-preserved smoothing filter was applied to the 100-kVp images to obtain denoised 100-kVp images. The mixed, 140-kVp, 100-kVp, and denoised 100-kVp images were assessed using contrast-to-noise ratio (CNR), and their diagnostic performance in comparison with MRI and infarcted volumes were evaluated. Three hundred four segments of 19 patients were evaluated. Fifty-three segments showed LGE in MRI. The median CNR of the mixed, 140-, 100-kVp and denoised 100-kVp images was 3.49, 1.21, 3.57, and 6.08, respectively. The median CNR was significantly higher in the denoised 100-kVp images than in the other three images (P < 0.05). The denoised 100-kVp images showed the highest diagnostic accuracy and sensitivity. The percentage of myocardium in the four CT image types was significantly correlated with the respective MRI findings. The use of a denoise filter with a low-kVp image can improve CNR, sensitivity, and accuracy in LIE-CT.