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Background: Falls among the elderly are a major societal problem. While observations of medium-distance walking using inertial sensors identified potential fall predictors, classifying individuals at risk based on single gait cycles remains elusive. This challenge stems from individual variability and step-to-step fluctuations, making accurate classification difficult., Methods: We recruited 44 participants, equally divided into high and low fall-risk groups. A smartphone secured on their second sacral spinous process recorded data during indoor walking. Features were extracted at each gait cycle from a 6-dimensional time series (tri-axial angular velocity and tri-axial acceleration) and classified using the gradient boosting decision tree algorithm., Findings: Mean accuracy across five-fold cross-validation was 0.936. "Age" was the most influential individual feature, while features related to acceleration in the gait direction held the highest total relative importance when aggregated by axis (0.5365)., Interpretation: Combining acceleration, angular velocity data, and the gradient boosting decision tree algorithm enabled accurate fall risk classification in the elderly, previously challenging due to lack of discernible features. We reveal the first-ever identification of three-dimensional pelvic motion characteristics during single gait cycles in the high-risk group. This novel method, requiring only one gait cycle, is valuable for individuals with physical limitations hindering repetitive or long-distance walking or for use in spaces with limited walking areas. Additionally, utilizing readily available smartphones instead of dedicated equipment has potential to improve gait analysis accessibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Multiple myeloma reduces cellular and humoral immunity. Optimal prediction of antibody response to anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients with MM and related disorders is essential to prevent coronavirus disease 2019 (COVID-19) during the SARS-CoV-2 pandemic. This study analyzed the humoral response to the anti-SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine and its associated factor in 83 patients from June to November 2021 at seven member institutions of the Kyoto Clinical Hematology Study Group. SARS-CoV-2 neutralizing antibody (nAb) was measured from 12 to 210 days. The result revealed that 40 (48.2%) patients with MM and 59 (100%) healthy controls became seropositive after vaccination. Receiver operating characteristic curve analysis identified serum immunoglobulin (Ig) M of > 18 mg/dL at vaccination as the optimal threshold level associated with seropositivity in the whole cohort. Moreover, the multivariate analysis identified serum IgM of > 18 mg/dL as the independent predictor for a favorable response. Serum IgA level was positively associated with vaccine response in a sub-cohort. Our findings indicate a significant association between immunoparesis and impaired humoral response against mRNA vaccination, including that against SARS-CoV-2, and that serum non-M-protein Ig levels can serve as surrogate biomarkers of nAb production ability., (© 2023. Japanese Society of Hematology.)

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS., Competing Interests: TF has received honoraria from Takeda Pharmaceutical; TT has received honoraria from Bristol Myers Squibb (BMS), Janssen Pharmaceutical, Sanofi, Kyowa Kirin and Chugai Pharmaceutical; YS has received honoraria from Ono Pharmaceutical, BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, Takeda Pharmaceutical and Chugai Pharmaceutical; SM has received honoraria from Sanofi and Ono Pharmaceutical; and NU has received honoraria from BMS and Takeda. JK is a consultant for Janssen Pharmaceutical, Abbvie and BMS; has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Shionogi and BMS; and has received honoraria from Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi and BMS. None of the pharmaceutical companies aforementioned benefited from the present research or played any role in our study. All other authors declare that they have no competing interests., (Copyright: © Inoue et al.)

Objective: The medial meniscus extrusion (MME) is associated with increased stress on the knee joint, which leads to cartilage degeneration. To evaluate the etiology of knee osteoarthritis, it is extremely important to create animal models of the disease that more closely resemble actual clinical conditions in terms of symptomatology, molecular biology, and histology. This study aimed to create a clinically relevant model of MME in rats., Design: Behavioral, molecular biological, and histological changes in the newly developed rat MME model were compared with those in sham and medial meniscus transection and medial collateral ligament transection (MMT) models to examine the characteristics of this model., Results: In the MME rat model, behavioral evaluation shows abnormalities in gait compared with the other 2 groups, and molecular biological evaluation of the infrapatellar synovia of rats shows that gene expression of inflammatory cytokines, matrix-degrading enzymes, and pain-related nerve growth factor was increased compared with the sham group. Furthermore, histological evaluation reveals that cartilage degeneration was the most severe in the MME group., Conclusions: The newly developed MME model reproduced the characteristic pathology of MME in clinical practice, such as severe pain, inflammation, and rapid progression of osteoarthritis. The MME model, which might more closely mimic human knee osteoarthritis (OA), could be a useful model for elucidating the pathophysiology and considering therapeutic management for knee OA., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The prognostic impact of patient-related factors, including age, nutritional parameters, and inflammation status, in higher-risk myelodysplastic syndromes (HR-MDS) has been largely unexplored. This multicenter retrospective study aimed to establish a real-world practice-based prognostic model for HR-MDS by considering both disease- and patient-related parameters in 233 patients treated with AZA monotherapy at seven institutions. We found that anemia, presence of circulating blasts in peripheral blood, low absolute lymphocyte count, low total cholesterol (T-cho) and albumin serum levels, complex karyotype, and del(7q) or  - 7 were poor prognostic factors. Therefore, we developed a new prognostic model called the Kyoto Prognostic Scoring System (KPSS) by incorporating the two variables with the highest C-indexes (complex karyotype and serum T-cho level). The KPSS classified patients into the following three groups: good (0 risk factors), intermediate (1), and poor (2). Median overall survival for these groups was 24.4, 11.3, and 6.9, respectively (p < 0.001). The discriminatory power of the KPSS was higher than that of the traditional International Prognostic Scoring System. In conclusion, we identified several nutritional parameters with prognostic relevance in patients with HR-MDS and generated a prognostic model consisting of complex karyotype and serum T-cho level that enabled excellent risk stratification., (© 2023. Japanese Society of Hematology.)

In order to determine the self-diffusion coefficients D of all the species in the solutions at 298.2 K, 1 H and 19 F NMR diffusion ordered spectroscopy (DOSY) has been conducted on coumarin 153 (C153) in binary mixed solvents of an imidazolium-based ionic liquid (IL), 1-dodecyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (C 12 mimTFSA), with three molecular liquids (MLs) of chloroform (CL), benzene (BZ), and propylene carbonate (PC) as a function of ML mole fraction x ML . Below x ML ≈ 0.8, the D values of each species do not significantly depend on the MLs. However, above this mole fraction, the diffusion of C153 becomes smoother in the order of BZ ≈ CL > PC systems. The interactions among C153, C 12 mim + , TFSA - , and ML molecules have been investigated using infrared (IR) and 1 H and 13 C NMR spectroscopic techniques. The relations of the diffusion of the species with the interactions among them have been discussed on the molecular scale. In the IL solution, the C153 carbonyl oxygen atom is hydrogen-bonded with the imidazolium ring C 2 -H atom of C 12 mim + . C 12 mim + also forms an ion pair with TFSA - . Thus, C153, C 12 mim + , and TFSA - cooperatively move in the CL and BZ solutions at a lower ML content, x ML < ∼0.8. On the other hand, at a higher ML content, x ML > ∼0.8, the C153 molecule diffuses with CL and BZ molecules because of the hydrogen bonding between the C153 carbonyl O atom and the CL H atom and the π-π interaction between the C153 and BZ ring planes, respectively. For the PC system, the change in the relative self-diffusion coefficients of each species with increasing x ML differs from those for the CL and BZ systems because of both hydrogen bonding donor H and acceptor O atoms of PC for C153, the IL cation and anion, and PC themselves.

Purpose: Spinal fusion surgery is often performed with pelvic fixation to prevent distal junctional kyphosis. The inclusion of spinopelvic fixation has been reported to induce progression of hip joint arthropathy in a radiographic follow-up study. However, its biomechanical mechanism has not yet been elucidated. This study aimed to compare the changes in hip joint moment before and after spinal fusion surgery., Methods: This study was an observational study and included nine patients (eight women and one man) who were scheduled to undergo spinopelvic fusion surgery. We calculated the three-dimensional external joint moments of the hip during gait, standing, and climbing stairs before and 1 year after surgery., Results: During gait, the maximum extension moment was 0.51 ± 0.29 and 0.63 ± 0.40 before and after spinopelvic fusion surgery (p = 0.011), and maximum abduction moment was 0.60 ± 0.33 and 0.83 ± 0.34 before and after surgery (p = 0.004), respectively. During standing, maximum extension moment was 0.76 ± 0.32 and 1.04 ± 0.21 before and after spinopelvic fusion surgery (p = 0.0026), and maximum abduction moment was 0.12 ± 0.20 and 0.36 ± 0.22 before and after surgery (p = 0.0005), respectively. During climbing stairs, maximum extension moment was - 0.31 ± 0.30 and - 0.48 ± 0.15 before and after spinopelvic fusion surgery (p = 0.040), and maximum abduction moment was 0.023 ± 0.18 and - 0.02 ± 0.13 before and after surgery (p = 0.038), respectively., Conclusion: This study revealed that hip joint flexion-extension and abduction-adduction moments increased after spinopelvic fixation surgery in the postures of standing, walking, and climbing stairs. The mechanism was considered to be adjacent joint disease after spinopelvic fusion surgery including sacroiliac joint fixation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Anti-CD20 monoclonal antibodies (MoAbs), rituximab (RIT), and obinutuzumab (OBZ) are the central components of immunochemotherapy for B-cell lymphoma (BCL). However, these agents potentially cause B-cell depletion, resulting in the impairment of antibody (Ab) production. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the optimal prediction of Ab response against anti-SARS-CoV-2 vaccination is critically important in patients with BCL treated by B-cell depletion therapeutics to prevent coronavirus disease 2019 (COVID-19)., Patients and Methods:  We investigated the effect of using RIT and/or OBZ on the Ab response in 131 patients with various types of BCL who received the second SARS-CoV-2 mRNA vaccine either after, during, or before immunochemotherapy containing B-cell-depleting moiety between June and November 2021 at seven institutes belonging to the Kyoto Clinical Hematology Study Group. The SARS-Cov-2 neutralizing Ab (nAb) was measured from 14 to 207 days after the second vaccination dose using the iFlash3000 automatic analyzer and the iFlash-2019-nCoV Nab kit., Results: Among 86 patients who received the vaccine within 12 months after B-cell depletion therapy, 8 (9.3%) were seropositive. In 30 patients who received the vaccine after 12 months from B-cell depletion therapy, 22 (73%) were seropositive. In 15 patients who were subjected to B-cell depletion therapy after vaccination, 2 (13%) were seropositive. The multivariate analysis indicated that an interval of 12 months between B-cell depletion therapy and the subsequent vaccination was significantly associated with effective Ab production. Receiver operating characteristic curve analysis identified the optimal threshold period after anti-CD20 MoAb treatment, which determines the seropositivity against SARS-CoV-2, to be 342 days., Conclusion: The use of anti-CD20 MoAb within 12 months before vaccination is a critical risk for poor Ab response against anti-SARS-CoV-2 vaccination in patients with BCL., Competing Interests: Y. M-K. has received honoraria from Bristol-Myers Squibb (BMS) and Janssen Pharmaceutical. S.M. has received honoraria from Sanofi and Ono Pharmaceutical. T.T. has received honoraria from BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, and Chugai Pharmaceutical. D.N. has received honoraria from Janssen Pharmaceutical and Chugai Pharmaceutical. K.S. has received honoraria from Chugai Pharmaceutical and Sanofi. T.K. has received honoraria from BMS, Ono Pharmaceutical, Chugai Pharmaceutical, Sanofi, and Janssen Pharmaceutical. N.U. has received honoraria from BMS, Janssen Pharmaceutical and Takeda. Y.S. has received honoraria from Ono Pharmaceutical, BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, Takeda Pharmaceutical, and Chugai Pharmaceutical. J.K. is a consultant for Janssen Pharmaceutical and BMS and has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, Takeda Pharmaceutical, and Mochida Pharmaceutical and has received honoraria from Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, BMS, and Takeda Pharmaceutical. All other authors have no conflicts of interest in this work., (© 2023 Onishi et al.)

Purpose: This study aimed to evaluate the progression of hip pathology and risk factors after ASD surgery., Methods: This case-control study enrolled 123 patients (246 hips); seven hips underwent hip arthroplasty were excluded. We measured the center-edge (CE) angle, joint space width (JSW), and Kellgren-Lawrence (KL) grade. We defined a CE angle˂25° as developmental dysplasia of the hip (DDH). We evaluated S2 alar-iliac (AI) screw loosening at final follow-up., Results: The annual decrease in the JSW was 0.31 mm up to 1 year, and 0.13 mm after 1 year (p = 0.001). KL grade progression occurred in 24 hips (10.0%; group P), while no progression occurred in 215 (90.0%; group N) hips. Nonparametric analysis between groups P and N revealed that significant differences were observed in sex, DDH, KL grade, ratio of S2AI screw fixation at baseline, and ratio of S2AI screw loosening at final follow-up. Multiple logistic regression analysis revealed that DDH (p = 0.018, odds ratio (OR) = 3.0, 95%CI = 1.2-7.3), baseline KL grade (p < 0.0001, OR = 37.7, 95%CI = 7.0-203.2), and S2AI screw fixation (p = 0.035, OR = 3.4, 95%CI = 1.1-10.4) were significant factors. We performed sub-analysis to elucidate the relationship between screw loosening and hip osteoarthritis in 131 hips that underwent S2AI screw fixation. Non-loosening of the S2AI screw was a significant factor for KL grade progression (p < 0.0001, OR = 8.9, 95%CI = 3.0-26.4)., Conclusion: This study identified the prevalence and risk factors for the progression of hip osteoarthritis after ASD surgery. Physicians need to pay attention to the hip joint pathology after ASD surgery., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Although it has been recognized that the medial meniscus extrusion (MME) leads to progressive cartilage loss and osteoarthritis (OA), about 20% of cases with MME had minor symptoms and poor progression of knee OA. However, it is still unclear which patients will have minimal symptoms or will not progress to degeneration. The purpose of this study is to compare the effect of the relationship between the MME and Joint line convergence angle (JLCA) on knee stress with the finite element (FE) analysis method., Methods: The 65 year-old female was taken computer tomography (CT) from thigh to ankle. A 3-dimentional nonlinear FE model was constructed from the patient's DICOM data. We made the six models, which was different from JLCA and MME. Contact stresses on the surfaces between femoral and tibial cartilages and both side of meniscus are analyzed., Results: As the JLCA or MME increased, the stress load on the medial compartment increased. The effect of MME was stronger on the femoral side, while the effect of JLCA was stronger for the tibia and meniscus. If the JLCA was tilted valgus, the stress in the medial compartment did not increase even in the presence of MME., Conclusions: This study revealed that the MME is associated with increased a stress loading on medial compartment structures. Furthermore, this change was enhanced by the varus tilt of the JLCA. In the case of valgus alignment, the contact pressure of the medial compartment did not increase so much even if with the MME., Level of Evidence: Level V., (© 2022. The Author(s).)

Introduction: Adult spinal fusion surgery improves lumbar alignment and patient satisfaction. Adult spinal deformity surgery improves saggital balance not only lumbar lesion, but also at hip joint coverage. It was expected that hip joint coverage rate was improved and joint stress decreased. However, it was reported that adjacent joint disease at hip joint was induced by adult spinal fusion surgery including sacroiliac joint fixation on an X-ray study. The mechanism is still unclear. We aimed to investigate the association between lumbosacral fusion including sacroiliac joint fixation and contact stress of the hip joint., Methods: A 40-year-old woman with intact lumbar vertebrae underwent computed tomography. A three-dimensional nonlinear finite element model was constructed from the L4 vertebra to the femoral bone with triangular shell elements (thickness, 2 mm; size, 3 mm) for the cortical bone's outer surface and 2-mm (lumbar spine) or 3-mm (femoral bone) tetrahedral solid elements for the remaining bone. We constructed the following four models: a non-fusion model (NF), a L4-5 fusion model (L5F), a L4-S1 fusion model (S1F), and a L4-S2 alar iliac screw fixation model (S2F). A compressive load of 400 N was applied vertically to the L4 vertebra and a 10-Nm bending moment was additionally applied to the L4 vertebra to stimulate flexion, extension, left lateral bending, and axial rotation. Each model's hip joint's von Mises stress and angular motion were analyzed., Results: The hip joint's angular motion in NF, L5F, S1F, and S2F gradually increased; the S2F model presented the greatest angular motion., Conclusions: The average and maximum contact stress of the hip joint was the highest in the S2F model. Thus, lumbosacral fusion surgery with sacroiliac joint fixation placed added stress on the hip joint. We propose that this was a consequence of adjacent joint spinopelvic fixation. Lumbar-to-pelvic fixation increases the angular motion and stress at the hip joint., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2022 The Japanese Society for Spine Surgery and Related Research.)

Background and Objectives: Gait can be severely affected by pain, muscle weakness, and aging resulting in lameness. Despite the high incidence of lameness, there are no studies on the features that are useful for classifying lameness patterns. Therefore, we aimed to identify features of high importance for classifying population differences in lameness patterns using an inertial measurement unit mounted above the sacral region., Methods: Features computed exhaustively for multidimensional time series consisting of three-axis angular velocities and three-axis acceleration were carefully selected using the Benjamini-Yekutieli procedure, and multiclass classification was performed using LightGBM (Microsoft Corp., Redmond, WA, USA). We calculated the relative importance of the features that contributed to the classification task in machine learning., Results: The most important feature was found to be the absolute value of the Fourier coefficients of the second frequency calculated by the one-dimensional discrete Fourier transform for real input. This was determined by the fast Fourier transformation algorithm using data of a single gait cycle of the yaw angular velocity of the pelvic region., Conclusions: Using an inertial measurement unit worn over the sacral region, we determined a set of features of high importance for classifying differences in lameness patterns based on different factors. This completely new set of indicators can be used to advance the understanding of lameness., Competing Interests: The authors have declared that no competing interests exist.

Accurate gluteus medius (GMd) volume evaluation may aid in the analysis of muscular atrophy states and help gain an improved understanding of patient recovery via rehabilitation. However, the segmentation of muscle regions in GMd images for cubic muscle volume assessment is time-consuming and labor-intensive. This study automated GMd-region segmentation from the computed tomography (CT) images of patients diagnosed with hip osteoarthritis using deep learning and evaluated the segmentation accuracy. To this end, 5250 augmented pairs of training data were obtained from five participants, and a conditional generative adversarial network was used to identify the relationships between the image pairs. Using the preserved test datasets, the results of automatic segmentation with the trained deep learning model were compared to those of manual segmentation in terms of the dice similarity coefficient (DSC), volume similarity (VS), and shape similarity (MS). As observed, the average DSC values for automatic and manual segmentations were 0.748 and 0.812, respectively, with a significant difference (p < 0.0001); the average VS values were 0.247 and 0.203, respectively, with no significant difference (p = 0.069); and the average MS values were 1.394 and 1.156, respectively, with no significant difference (p = 0.308). The GMd volumes obtained by automatic and manual segmentation were 246.2 cm3 and 282.9 cm3, respectively. The noninferiority of the DSC obtained by automatic segmentation was verified against that obtained by manual segmentation. Accordingly, the proposed GAN-based automatic GMd-segmentation technique is confirmed to be noninferior to manual segmentation. Therefore, the findings of this research confirm that the proposed method not only reduces time and effort but also facilitates accurate assessment of the cubic muscle volume., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Recently, the number of adult spinal deformity surgeries including sacroiliac joint fixation (SIJF) by using an S2 alar iliac screw or iliac screw has increased to avoid the distal junctional failure. However, we occasionally experienced patients who suffered from hip pain after a long instrumented spinal fusion. We hypothesized that long spinal fusion surgery including SIJF influenced the hip joint as an adjacent joint. The aim of this paper was to evaluate the association between spinal deformity surgery including SIJF and radiographic progression of hip osteoarthritis (OA)., Methods: This study was retrospective cohort study. In total, 118 patients who underwent spinal fusion surgery at single center from January 2013 to August 2018 were included. We measured joint space width (JSW) at central space of the hip joint. We defined reduction of more than 0.5 mm/year in JSW as hip OA progression. The patients were divided into two groups depending on either a progression of hip osteoarthritis (Group P), or no progression (Group N)., Results: The number of patients in Group P and Group N was 47 and 71, respectively. Factor that was statistically significant for hip OA was SIJF (p = 0.0065, odds ratio = 7.1, 95% confidence interval = 1.6-31.6). There were no other significant differences by the multiple logistic regression analysis., Conclusion: This study identified spinal fixation surgery that includes SIJF as a predictor for radiographic progression of hip OA over 12 months. We should pay attention to hip joint lesions after adult spinal deformity surgery, including SIJF.

Multiple myeloma (MM) is cytogenetically, genetically and molecularly heterogenous even among subclones in one patient, therefore, it is essential to identify both frequent and patient-specific drivers of molecular abnormality. Following previous molecular investigations, we in this study investigated the expression patterns and function of the Ewing sarcoma breakpoint region 1 (EWSR1) gene in MM. The EWSR1 transcriptional level in CD138-positive myeloma cells was higher in 36.4% of monoclonal gammopathy of undetermined significance, in 67.4% of MM patients compared with normal plasma cells, and significantly higher in ten human myeloma-derived cell lines (HMCLs) examined. EWSR1 gene knockdown caused growth inhibition with an increase of apoptotic cells in NCI-H929 and KMS-12-BM cells. Gene expression profiling using microarray analysis suggested EWSR1 gene knockdown caused transcriptional modulation of several genes associated with processes such as cell proliferation, cell motility, cell metabolism, and gene expression. Of particular, EWSR1 gene knockdown caused upregulation of let-7c and downregulation of its known targets K-RAS and AKT. Finally, our analysis using community database suggested that high EWSR1 expression positively associates with poor prognosis and advanced disease stage in MM. These findings suggest that EWSR1 overexpression is a pro-oncogenic molecular abnormality that may participate in MM progression.

An increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) is associated with disease progression and treatment resistance in multiple myeloma (MM). We investigated the mechanisms underlying MDSC induction, and sought to discover a strategy for prevention of MDSC induction in MM. Using a transwell co-culture system, four of nine examined human myeloma-derived cell lines (HMCLs) were potent in inducing monocytic (M)-MDSCs from normal peripheral blood mononuclear cells (PBMCs). As the results, we identified that secretion of C-C motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) by myeloma cells is a prerequisite for induction of MDSCs in MM. The immunomodulatory drug (IMiD) compounds, such as lenalidomide (LEN) and pomalidomide (POM), were identified as potent inhibitors of MDSC induction through bidirectional molecular effects of cereblon (CRBN)-dependent and -independent downregulation of CCL5 and MIF in myeloma cells; and downregulation of C-C motif chemokine receptor 5, a receptor for CCL5, and induction of interferon regulatory factor 8, a critical transcription factor for monocytic differentiation, in PBMCs. In the present study of the molecular mechanisms underlying MDSC induction, we identified a novel effect of LEN and POM of inhibiting MDSC induction via overlapping regulatory effects in myeloma cells and normal PBMCs., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Chromosome instability (CIN), the hallmarks of cancer, reflects ongoing chromosomal changes caused by chromosome segregation errors and results in whole chromosomal or segmental aneuploidy. In multiple myeloma (MM), CIN contributes to the acquisition of tumor heterogeneity, and thereby, to disease progression, drug resistance, and eventual treatment failure; however, the underlying mechanism of CIN in MM remains unclear. Faithful chromosomal segregation is tightly regulated by a series of mitotic checkpoint proteins, such as budding uninhibited by benzimidazoles 1 (BUB1). In this study, we found that BUB1 was overexpressed in patient-derived myeloma cells, and BUB1 expression was significantly higher in patients in an advanced stage compared to those in an early stage. This suggested the involvement of aberrant BUB1 overexpression in disease progression. In human myeloma-derived cell lines (HMCLs), BUB1 knockdown reduced the frequency of chromosome segregation errors in mitotic cells. In line with this, partial knockdown of BUB1 showed reduced variations in chromosome number compared to parent cells in HMCLs. Finally, BUB1 overexpression was found to promote the clonogenic potency of HMCLs. Collectively, these results suggested that enhanced BUB1 expression caused an increase in mitotic segregation errors and the resultant emergence of subclones with altered chromosome numbers and, thus, was involved in CIN in MM.

RSK2 is a serine/threonine kinase downstream signaling mediator in the RAS/ERK signaling pathway and may be a therapeutic target in mantle cell lymphoma (MCL), an almost incurable disease subtype of non-Hodgkin lymphoma. In this study, serine-227 (RSK2 Ser227 ) in the N-terminal kinase domain (NTKD) of RSK2 was found to be ubiquitously active in five MCL-derived cell lines and in tumor tissues derived from five MCL patients. BI-D1870, an inhibitor specific to RSK2-NTKD, caused RSK2 Ser227 dephosphorylation, and thereby, induced dose-dependent growth inhibition via G 2 /M cell cycle blockade and apoptosis in four of the five cell lines, while one cell line showed only modest sensitivity. In addition, RSK2 gene knockdown caused growth inhibition in the four BI-D1870-sensitive cell lines. Comparative gene expression profiling of the MCL-derived cell lines showed that inhibition of RSK2 Ser227 by BI-D1870 caused downregulation of oncogenes, such as c-MYC and MYB; anti-apoptosis genes, such as BCL2 and BCL2L1; genes for B cell development, including IKZF1, IKZF3, and PAX5; and genes constituting the B cell receptor signaling pathway, such as CD19, CD79B, and BLNK. These findings show that targeting of RSK2 Ser227 enables concomitant blockade of pathways that are critically important in B cell tumorigenesis. In addition, we found favorable combinatory growth inhibitory effects of BI-D1870 with inhibitors of BTK (ibrutinib), AKT (ipatasertib), and BCL2 (venetoclax) in cell characteristic-dependent manners. These results provide a rationale for RSK2 Ser227 in the NTKD as a potential therapeutic target in MCL and for future development of a novel bioavailable RSK2 NTKD-specific inhibitor., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Hip dislocation rates in patients with combined total hip arthroplasty (THA) and spinal deformity fixation are significantly higher than those of THA alone. Nevertheless, there are no treatment recommendations for patients who undergo THA and require a spine deformity correction later., Methods: Twenty-eight patients underwent spinal fixation surgery for adult spinal deformity. Sagittal spinopelvic alignment was analyzed on lateral radiographs taken preoperatively and postoperatively in the sitting and standing positions. Univariate linear regression analysis was conducted to identify the factors affecting the pelvic inclination in the sitting position after spinal fixation. Multiple regression analysis was conducted to determine the most efficient combination of radiographic parameters for predicting postoperative pelvic inclination while sitting., Results: There were significantly weak associations between postoperative sacral slope (SS) in the sitting position and the following factors: the number of vertebral levels fused (β = 0.30, p = 0.003); the presence of sacral fixation (β = 0.22, p = 0.01); the presence of sacroiliac joint fixation (β = 0.24, p = 0.008); and preoperative SS while standing and sitting (β = 0.21, p = 0.01 and β = 0.34, p = 0.001). Postoperative lumbar lordosis (LL) while standing was strongly associated with postoperative SS in the sitting position (β = 0.67, p <.0001). The combination of postoperative LL in the standing position and preoperative SS in the sitting position was the best fit, and the adjusted R-squared was 0.82., Conclusions: We devised a prediction formula for pelvic inclination while sitting after spinal fixation that has high predictability: postoperative SS while sitting = 11.7+ (0.4 × postoperative planned LL while standing) + (0.16 × preoperative SS while sitting). This study could be the basis for treatment recommendations for patients who have undergone THA and require a spine deformity correction later., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2020 by The Japanese Society for Spine Surgery and Related Research.)

Chromosomal microdeletions frequently cause loss of prognostically relevant tumor suppressor genes in hematologic malignancies; however, detection of minute deletions by conventional methods for chromosomal analysis, such as G-banding and fluorescence in situ hybridization (FISH), is difficult due to their low resolution. Here, we describe a new diagnostic modality that enables detection of chromosomal microdeletions, using CDKN2A gene deletion in B cell lymphomas (BCLs) as an example. In this method, which we refer to as amplified-FISH (AM-FISH), a 31-kb fluorescein isothiocyanate (FITC)-conjugated DNA probe encoding only CDKN2A was first hybridized with the chromosome, and then labeled with Alexa Fluor 488-conjugated anti-FITC secondary antibody to increase sensitivity. CDKN2A signals were equally identifiable by AM-FISH and conventional FISH in normal mononuclear blood cells. In contrast, when two BCL cell lines lacking CDKN2A were analyzed, CDKN2A signals were not detected by AM-FISH, whereas conventional FISH yielded false signals. Furthermore, AM-FISH detected CDKN2A deletions in two BCL patients with 9p21 microdeletions, which were not detected by conventional FISH. These results suggest that AM-FISH is a highly sensitive, specific, and simple method for diagnosis of chromosomal microdeletions.

Acetyl-Coenzyme A carboxylase (ACC), malonyl-CoA reductase (MCR), and malonic semialdehyde reductase (MRS) convert HCO 3 - and acetyl-CoA into 3-hydroxypropionate (3HP) in the 3-hydroxypropionate/4-hydroxybutyrate carbon fixation cycle resident in the extremely thermoacidophilic archaeon Metallosphaera sedula. These three enzymes, when introduced into the hyperthermophilic archaeon Pyrococcus furiosus, enable production of 3HP from maltose and CO 2 . Sub-optimal function of ACC was hypothesized to be limiting for production of 3HP, so accessory enzymes carbonic anhydrase (CA) and biotin protein ligase (BPL) from M. sedula were produced recombinantly in Escherichia coli to assess their function. P. furiosus lacks a native, functional CA, while the M. sedula CA (Msed&#95;0390) has a specific activity comparable to other microbial versions of this enzyme. M. sedula BPL (Msed&#95;2010) was shown to biotinylate the β-subunit (biotin carboxyl carrier protein) of the ACC in vitro. Since the native BPLs in E. coli and P. furiosus may not adequately biotinylate the M. sedula ACC, the carboxylase was produced in P. furiosus by co-expression with the M. sedula BPL. The baseline production strain, containing only the ACC, MCR, and MSR, grown in a CO 2 -sparged bioreactor reached titers of approximately 40 mg/L 3HP. Strains in which either the CA or BPL accessory enzyme from M. sedula was added to the pathway resulted in improved titers, 120 or 370 mg/L, respectively. The addition of both M. sedula CA and BPL, however, yielded intermediate titers of 3HP (240 mg/L), indicating that the effects of CA and BPL on the engineered 3HP pathway were not additive, possible reasons for which are discussed. While further efforts to improve 3HP production by regulating gene dosage, improving carbon flux and optimizing bioreactor operation are needed, these results illustrate the ancillary benefits of accessory enzymes for incorporating CO 2 into 3HP production in metabolically engineered P. furiosus, and hint at the important role that CA and BPL likely play in the native 3HP/4HB pathway in M. sedula. Biotechnol. Bioeng. 2016;113: 2652-2660. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

A gold-catalyzed cyclization of 1-propargyl-1,2,3,4-tetrahydro-β-carboline led to formation the D-ring of strictamine. Functional group modifications of the resulting tetracyclic indolenine led to the formal total synthesis of (±)-strictamine.

A series of novel 3,4,7-trisubstituted benzofuran derivatives were synthesized, and their binding affinity to κ- (KOR) and μ-opioid receptors (MOR) were evaluated. Several aryl ethers showed moderate binding activities to KOR (IC50=3.9-11 µM) without binding to MOR.

Objective: This study aimed to evaluate the effects of establishing a Department of General Internal Medicine (DGIM) on the length of hospitalization. We evaluated the length of hospitalization associated with diseases for which full-time specialists were not available and were instead treated by physicians of the DGIM after its establishment., Methods: A retrospective cohort study was conducted with a review of the subjects' medical records. The subjects included patients ≥16 years of age who were hospitalized with pneumonia or cerebral infarction and treated by a physician with a specialty in internal medicine as the disease outside their specialty prior to DGIM establishment (October 1, 2006 to September 30, 2008) or by a physician of the DGIM after its establishment (October 1, 2009 to September 30, 2011). The primary outcome was the change in the length of hospitalization. The length of hospitalization for heart failure, which was treated by specialists (cardiologists) in both study periods, was also examined for comparison., Results: We evaluated 322 and 423 cases of pneumonia treated before and after the establishment of the DGIM, as well as 223 and 229 cases of cerebral infarction and 132 and 206 cases of heart failure, respectively. The length of hospitalization before and after establishment of the DGIM was 21.6 and 16.0 days for the pneumonia patients (p<0.001) and 24.2 and 19.9 days for the cerebral infarction patients (p<0.001), respectively. On the other hand, the change in the length of hospitalization for the heart failure patients was not statistically significant (19.9 vs. 17.6 days; p=0.281)., Conclusion: The establishment of the DGIM reduced the length of hospitalization associated with diseases for which full-time specialists were not available by over 17%.

Purpose: To investigate optimal flip angle (FA) of three-dimensional fat-suppressed T1-weighted image on Gd-EOB-DTPA-enhanced MRI., Methods: Forty-five patients with 35 hepatocellular carcinomas (HCCs) and 16 liver metastases (METs) were investigated. Signal-to-noise ratio (SNR), tumor-to-liver contrast (TLC) of HCC and MET, visual image quality (IQ) and lesion conspicuity (LeCo) were evaluated at hepatobiliary phase with different FAs (FA15°-30°-45°-60° in 13 patients, FA5°-10°-15°-20°-25° in 32 patients)., Results: TLC gradually showed better in range from FA15° to FA60° and FA5° to FA25°, but SNRs gradually decreased. SNR and TLC-MET at FA15° were significantly better than those at FA45° and FA60°. SNR at FA10° was significantly higher than at FA5°, FA20°, and FA25°. TLC-HCC and TLC-MET at FA5° were inferior to other FAs. IQs and LeCos at FA15° and FA30° were superior to those at FA45° and FA60°. IQs at FA5° and FA25° were significantly lower than those at FA10°-20°, although LeCos for HCC and MET at FA25° were superior to those at FA5°-20°., Conclusions: FA ranging from 10° to 20° is suitable for hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI, to image HCC and MET.

Tetrahydroquinoline (THQ) was deemed to be a suitable scaffold for our nonsteroidal selective androgen receptor modulator (SARM) concept. We adapted the strategy of switching the antagonist function of cyano-group-containing THQ (CN-THQ) to the agonist function and optimized CN-THQ as an orally available drug candidate with suitable pharmacological and ADME profiles. Based on binding mode analyses and synthetic accessibility, we designed and synthesized a compound that possesses a para-substituted aromatic ring attached through an amide linker. The long-tail THQ derivative 6-acetamido-N-(2-(8-cyano-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl)-2-methylpropyl)nicotinamide (1 d), which bears a para-acetamide-substituted aromatic group, showed an appropriate in vitro biological profile, as expected. We considered that the large conformational change at Trp741 of the androgen receptor (AR) and the hydrogen bond between 1 d and helix 12 of the AR could maintain the structure of the AR in its agonist form; indeed, 1 d displays strong AR agonistic activity. Furthermore, 1 d showed an appropriate in vivo profile for use as an orally available SARM, displaying clear tissue selectivity, with a separation between its desirable osteoanabolic effect on femoral bone mineral density and its undesirable virilizing effects on the uterus and clitoral gland in a female osteoporosis model., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: A new device for the treatment of femoral neck fractures that uses 2 cephalocervical screws in a sliding mechanism allowing linear intraoperative and postoperative compression has been developed. The purpose of this retrospective study was to determine the results using this device for the treatment of stable and unstable femoral neck fractures., Methods: Between November 2007 and November 2011, 61 consecutive skeletally mature patients with femoral neck fractures were treated with a new cephalocervical screw (Dual SC screw; KISCO DIR Co., Ltd., Kobe). All contactable patients were followed up for a minimum of 16 weeks postoperatively (range 16-123 weeks). Clinical and radiographic examinations were performed at the final evaluation. Healing and return to activities of daily living were used to evaluate outcomes., Results: There were 51 women and 10 men with a mean age of 80.8 years (range, 41-99). The average of surgical time was 33.1 min (21-66 min). One patient died, one was too infirm for follow-up, and eleven could not be located, leaving 48 patients available for final evaluation (78.7%). The overall incidence of nonunion was 10.4%. Fracture nonunion was less common for undisplaced fractures than for displaced fractures (1 of 21 [4.8%] vs. 4 of 27 [14.8%]). The mean amount of collapse of the neck was 5.45 mm (3.92 mm in undisplaced and 6.64 mm in displaced). Radiographic analysis at final evaluation revealed no implant failures. 62.5% of the patients recovered their prefracture status., Conclusion: The Dual SC screw device appears to be a reliable implant for the treatment of femoral neck fractures. Its design contributes to overcome the implant failures such as a medial migration, cut-out, or back-out; besides, the union rate of this implant was considered superior to that of existing systems. If the early shortening of the neck occurs after this surgery, the surgeons should be considered to keep them partially weight bearing or choose a replacement procedure for such patients.

Achiral meteoritic amino acids, glycine and alpha-methylalanine, with hydrogen isotope (D/H) chirality, acted as the source of chirality in asymmetric autocatalysis with amplification of ee to afford highly enantioenriched 5-pyrimidyl alkanols.

We have determined the crystal structure, at 1.2-A resolution, of Equisetum arvense ferredoxin isoform II (FdII), which lacks residues equivalent to Arg(39) and Glu(28) highly conserved among other ferredoxins (Fds). In other Fds these residues form an intramolecular salt bridge crucial for stabilization of the [2Fe-2S] cluster, which is disrupted upon complex formation with Fd-NADP(+) oxidoreductase (FNR) to form two intermolecular salt bridges. The overall structure of FdII resembles the known backbone structures of E. arvense isoform I (FdI) and other plant-type Fds. Dramatically, in the FdII structure a unique, alternative salt bridge is formed between Arg(22) and Glu(58). This results in a different relative orientation of the alpha-helix formed by Leu(23)-Glu(29) and eliminates the possibility of forming three of the five intermolecular salt bridges identified on formation of a complex between maize FdI and maize FNR. Mutation of FdII, informed by structural differences with FdI, showed that the alternative salt bridge and the absence of an otherwise conserved Tyr residue are important for the alternative stabilization of the FdII [2Fe-2S] cluster. We also investigated FdI and FdII electron transfer to FNR on chloroplast thylakoid membranes. The K(m) and V(max) values of FdII are similar to those of FdI, contrary to previous measurements of the reverse reaction, from FNR to Fd. The affinity between reduced FdI and oxidized FNR is much greater than that between oxidized FdI and reduced FNR, whereas this is not the case with FdII. The pH dependence of electron transfer by FdI, FdII, and an FdII mutant with FdI features was measured and further indicated that the binding mode to FNR differs between FdI and FdII. Based on this evidence, we hypothesize that binding modes with other Fd-dependent reductases may also vary between FdI and FdII. The structural differences between FdI and FdII therefore result in functional differences that may influence partitioning of electrons into different redox metabolic pathways.

In order to elucidate the importance of a ferredoxin (Fd) Arg-Glu pair involved in dynamic exchange from intra- to intermolecular salt bridges upon complex formation with ferredoxin-NADP(+) oxidoreductase (FNR), Equisetum arvense FdI and FdII were investigated as normal and the pair-lacking Fd, respectively. The FdI mutant lacking this pair was unstable and rapidly lost the [2Fe-2S] cluster. The catalytic constant (k(cat)) of the electron transfer for FdI is 5.5 times that for FdII and the introduction of this pair into FdII resulted in the increase of k(cat) to a level comparable to that for FdI, demonstrating directly that the Arg-Glu pair is important for efficient electron transfer between Fd and FNR.

Acute ethanol administration temporarily decreases the sensitivity to endotoxin (lipopolysaccharide, LPS) in the liver. The purpose of this study was to investigate the changes of toll-like receptor (TLR)-4, a newly identified LPS receptor in macrophages, in the liver following acute ethanol administration. Male C57BL/6N mice were given a bolus intragastric administration of ethanol (5 mg/g BW) through a gastric canula, and liver samples were obtained 2-48 h later. RAW264.7 macrophages were cultured in the presence of ethanol (100 mM) or LPS (10 ng/ml) for up to 4 h. TLR-4 mRNA in the liver and RAW264.7 cells was detected by RNase protection assay. As expected, TLR-4 mRNA was clearly detected in the control liver; however, it was barely detectable in the liver 2-6 h after ethanol administration, followed by the gradual increase to the basal levels 48 h later. Interestingly, LPS (10 ng/ml), but not ethanol (100 mM), decreased TLR-4 mRNA in RAW264.7 macrophages in 4 h. Indeed, gut-sterilization by oral antibiotics pretreatment prevented the decrease in TLR-4 mRNA caused by acute ethanol administration, supporting the hypothesis that gut-derived endotoxin is involved in the mechanism. These findings clearly indicated that acute ethanol administration in vivo down-regulates TLR-4 expression in the liver. This phenomenon most likely explains the mechanism by which acute ethanol blunts the response of Kupffer cells to LPS transiently.

Background: Hepatic stellate cells have been reported to play important roles in the regulation of hepatic microcirculation via cell contraction. Increase in intracellular calcium concentration is required to induce cell contraction. We have already reported the existence of L-type voltage-operated Ca2+ channels (VOCC), such as smooth muscle cells. On the other hand, alcohol has been known to disturb hepatic microcirculation. In this study, we evaluated the effect of acute and chronic treatment of alcohol on VOCC in rat hepatic stellate cells., Methods: Stellate cells isolated from rats were cultured with or without 100 mM ethanol for up to 14 days. VOCC were detected by the patch clamp technique. Cells cultured for 14 days without ethanol were exposed to ethanol to investigate calcium current during membrane depolarization. alpha-Smooth muscle actin (alpha-SMA) was stained by indirect immunofluorescence., Results: In the control model, VOCC were recognized in cells cultured for more than 7 days. Detection of VOCC increased from 9% on day 7 to 55% on day 14. On the other hand, VOCC in cells treated chronically with 100 mM ethanol appeared earlier than in the control and the incidences were significantly higher than those of the control accompanied with an early activation of cells. In contrast, simultaneous exposure to ethanol during the membrane depolarization inhibited Ca2+ current., Conclusions: The expression of Ca2+ channels in stellate cells were up-regulated by the chronic treatment of alcohol accompanied with the transformation to myofibroblast-like phenotype. However, alcohol itself inhibited Ca2+ current.