Publications by authors named "Takashi Sato"

680 Publications

Identification of conserved SARS-CoV-2 spike epitopes that expand public cTfh clonotypes in mild COVID-19 patients.

J Exp Med 2021 12 14;218(12). Epub 2021 Oct 14.

Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.

Adaptive immunity is a fundamental component in controlling COVID-19. In this process, follicular helper T (Tfh) cells are a subset of CD4+ T cells that mediate the production of protective antibodies; however, the SARS-CoV-2 epitopes activating Tfh cells are not well characterized. Here, we identified and crystallized TCRs of public circulating Tfh (cTfh) clonotypes that are expanded in patients who have recovered from mild symptoms. These public clonotypes recognized the SARS-CoV-2 spike (S) epitopes conserved across emerging variants. The epitope of the most prevalent cTfh clonotype, S864-882, was presented by multiple HLAs and activated T cells in most healthy donors, suggesting that this S region is a universal T cell epitope useful for booster antigen. SARS-CoV-2-specific public cTfh clonotypes also cross-reacted with specific commensal bacteria. In this study, we identified conserved SARS-CoV-2 S epitopes that activate public cTfh clonotypes associated with mild symptoms.
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http://dx.doi.org/10.1084/jem.20211327DOI Listing
December 2021

Daple deficiency causes hearing loss in adult mice by inducing defects in cochlear stereocilia and apical microtubules.

Sci Rep 2021 Oct 12;11(1):20224. Epub 2021 Oct 12.

Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

The V-shaped arrangement of hair bundles on cochlear hair cells is critical for auditory sensing. However, regulation of hair bundle arrangements has not been fully understood. Recently, defects in hair bundle arrangement were reported in postnatal Dishevelled-associating protein (ccdc88c, alias Daple)-deficient mice. In the present study, we found that adult Daple mice exhibited hearing disturbances over a broad frequency range through auditory brainstem response testing. Consistently, distorted patterns of hair bundles were detected in almost all regions, more typically in the basal region of the cochlear duct. In adult Daple mice, apical microtubules were irregularly aggregated, and the number of microtubules attached to plasma membranes was decreased. Similar phenotypes were manifested upon nocodazole treatment in a wild type cochlea culture without affecting the microtubule structure of the kinocilium. These results indicate critical role of Daple in hair bundle arrangement through the orchestration of apical microtubule distribution, and thereby in hearing, especially at high frequencies.
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http://dx.doi.org/10.1038/s41598-021-96232-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511111PMC
October 2021

Postoperative femoral anteroposterior position while standing correlates with the posterior tibial slope and posterior femoral condylar offset in medial pivot total knee arthroplasty.

Biomed Mater Eng 2021 Oct 6. Epub 2021 Oct 6.

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Science, Niigata, Niigata, Japan.

Background: After total knee arthroplasty (TKA), the femur tends to be located posteriorly under weight-bearing (WB) conditions, and a paradoxical femoral anterior motion occurs, leading to joint instability.

Objective: We aimed to clarify factors which affect the postoperative femoral anteroposterior position relative to the tibia under WB conditions (A-P position) in medial pivot (MP) TKA.

Methods: Among 126 knees (81 women) with primary TKA using MP prosthesis for varus osteoarthritic knees, 70 knees had cruciate-retaining inserts (CR) with the reduced conformity and 56 knees had cruciate-substituting inserts (CS) with the full conformity. Using the three-dimensional (3D) assessment system, the associations between the A-P position and the factors including pre- and postoperative lower extremity alignment, component positions, and posterior femoral condylar offset (PCO), were assessed regarding the type of inserts.

Results: Significant correlations were seen between the A-P position and posterior tibial slope (PTS), medial PCO, and lateral PCO. Regarding the difference between the two inserts, the PTS, medial PCO, and lateral PCO significantly correlated with the A-P position in the CR, but only the PTS correlated in the CS.

Conclusions: The increased PTS and decreased PCO were the dominant factors for the A-P position in MP TKA.
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http://dx.doi.org/10.3233/BME-211299DOI Listing
October 2021

Glycan engineering of the SARS-CoV-2 receptor-binding domain elicits cross-neutralizing antibodies for SARS-related viruses.

J Exp Med 2021 12 8;218(12). Epub 2021 Oct 8.

Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.

Broadly protective vaccines against SARS-related coronaviruses that may cause future outbreaks are urgently needed. The SARS-CoV-2 spike receptor-binding domain (RBD) comprises two regions, the core-RBD and the receptor-binding motif (RBM); the former is structurally conserved between SARS-CoV-2 and SARS-CoV. Here, in order to elicit humoral responses to the more conserved core-RBD, we introduced N-linked glycans onto RBM surfaces of the SARS-CoV-2 RBD and used them as immunogens in a mouse model. We found that glycan addition elicited higher proportions of the core-RBD-specific germinal center (GC) B cells and antibody responses, thereby manifesting significant neutralizing activity for SARS-CoV, SARS-CoV-2, and the bat WIV1-CoV. These results have implications for the design of SARS-like virus vaccines.
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http://dx.doi.org/10.1084/jem.20211003DOI Listing
December 2021

O-glycosylated HBsAg peptide can induce specific antibody neutralizing HBV infection.

Biochim Biophys Acta Gen Subj 2021 Sep 25;1866(1):130020. Epub 2021 Sep 25.

Molecular and Cellular Glycoproteomics Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan. Electronic address:

Background: Hepatitis B virus (HBV), which causes hepatitis, liver cirrhosis, and hepatocellular carcinoma, is a global human health problem. HBV contains three envelope proteins, S-, M-, and L-hepatitis B surface antigen (HBsAg). We recently found that O-glycosylated M-HBsAg, reactive with jacalin lectin, is one of the primary components of HBV DNA-containing virus particles. Thus, we aimed to analyze and target the glycosylation of HBsAg.

Methods: HBsAg prepared from the serum of Japanese patients with HBV were analyzed using mass spectrometry. The glycopeptide modified with O-glycan was generated and used for immunization. The specificity of the generated antibody and the HBV infection inhibition activity was examined.

Results: Mass spectrometry analysis revealed that T37 and/or T38 on M-HBsAg of genotype C were modulated by ±NeuAc(α2,3)Gal(β1,3)GalNAc. Chemically and enzymatically synthesized O-glycosylated peptide (Glyco-PS2) induced antibodies that recognize mainly PreS2 in M-HBsAg not in L-HBsAg, whereas the non-glycosylated peptide (PS2) induced antisera recognizing L-HBsAg but not O-glycosylated M-HBsAg. The removal of O-glycan from M-HBsAg partly decreased the reactivity of the Glyco-PS2 antibody, suggesting that peptide part was also recognized by the antibody. The antibody further demonstrated the inhibition of HBV infection in human hepatic cells in vitro.

Conclusions: Glycosylation of HBsAg occurs differently in different HBsAgs in a site-specific manner. The new Glyco-PS2 antibody, recognizing O-glycosylated M-HBsAg of genotype C, could inhibit HBV infection.

General Significance: The detailed analysis of HBsAg identified different glycosylations of HBV surface. The glycosylated peptide based on mass spectrometry analysis showed higher potential to induce functional antibody against HBV.
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http://dx.doi.org/10.1016/j.bbagen.2021.130020DOI Listing
September 2021

Longitudinal Assessment of Prognostic Understanding in Patients with Advanced Lung Cancer and Its Association with Their Psychological Distress.

Oncologist 2021 Sep 12. Epub 2021 Sep 12.

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Background: Accurate prognostic understanding in patients with advanced cancer is essential for shared decision making; however, patients may experience psychological burden through knowing the incurable nature of advanced cancer. It has been unclear how their prognostic understanding fluctuates and whether accurate prognostic understanding is associated with psychological distress from the time of diagnosis over time.

Materials And Methods: We longitudinally investigated prognostic understanding in 225 patients with newly diagnosed advanced lung cancer at 16 hospitals in Japan until 24 months after diagnosis. We examined associated factors with being consistently accurate in prognostic understanding, especially focusing on its association with psychological well-being.

Results: The proportion of patients with an inaccurate prognostic understanding remained approximately 20% over time with the presence of patients with inconsistent understanding. Patients with consistently accurate prognostic understanding showed a significantly lower Emotional Well-Being subscale score at both 3 and 6 months after diagnosis (p = .010 and p = .014, respectively). In multivariate analyses, being consistently accurate in prognostic understanding was significantly associated with female gender and higher lung cancer-specific symptom burden at 3 months (p = .008 and p = .005, respectively) and lower emotional well-being at 6 months (p = .006).

Conclusion: Although substantial proportions of patients with advanced lung cancer had inaccurate prognostic understanding from the time of diagnosis over time, patients with consistently accurate prognostic understanding experienced greater psychological burden. Our findings highlight the importance of continuous psychological care and support for patients who understand their severe prognosis accurately.

Implications For Practice: This study demonstrated that approximately 20% of patients with advanced lung cancer had an inaccurate understanding about their prognosis, not only at the time of diagnosis but also at the later time points. Being consistently accurate in prognostic understanding was significantly associated with elevated levels of psychological distress. Although accurate prognostic understanding is essential for decision making for treatment and advance care planning, health care providers should be aware of psychological burdens in patients that accept their severe prognosis accurately. Appropriate care and support for such patients are warranted from diagnosis over time.
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http://dx.doi.org/10.1002/onco.13973DOI Listing
September 2021

Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice.

Diabetologia 2021 Sep 9. Epub 2021 Sep 9.

Laboratory of Developmental Biology & Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.

Aims/hypothesis: Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells.

Methods: We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin.

Results: Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12-15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca signalling response and were increased in number in experimental diabetes models.

Conclusions/interpretation: Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes.

Data Availability: The single-cell RNA sequence (scRNA-seq) analysis datasets generated in this study have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE166164 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166164 ).
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http://dx.doi.org/10.1007/s00125-021-05560-xDOI Listing
September 2021

A Canonical Scheme of Bottom-Up and Top-Down Information Flows in the Frontoparietal Network.

Front Neural Circuits 2021 12;15:691314. Epub 2021 Aug 12.

Department of Physiology, Monash University, Clayton, VIC, Australia.

Goal-directed behavior often involves temporal separation and flexible context-dependent association between sensory input and motor output. The control of goal-directed behavior is proposed to lie in the frontoparietal network, but the computational architecture of this network remains elusive. Based on recent rodent studies that measured and manipulated projection neurons in the frontoparietal network together with findings from earlier primate studies, we propose a canonical scheme of information flows in this network. The parietofrontal pathway transmits the spatial information of a sensory stimulus or internal motor bias to drive motor programs in the frontal areas. This pathway might consist of multiple parallel connections, each controlling distinct motor effectors. The frontoparietal pathway sends the spatial information of cognitively processed motor plans through multiple parallel connections. Each of these connections could support distinct spatial functions that use the motor target information, including attention allocation, multi-body part coordination, and forward estimation of movement state (i.e., forward models). The parallel pathways in the frontoparietal network enable dynamic interactions between regions that are tuned for specific goal-directed behaviors. This scheme offers a promising framework within which the computational architecture of the frontoparietal network and the underlying circuit mechanisms can be delineated in a systematic way, providing a holistic understanding of information processing in this network. Clarifying this network may also improve the diagnosis and treatment of behavioral deficits associated with dysfunctional frontoparietal connectivity in various neurological disorders including Alzheimer's disease.
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http://dx.doi.org/10.3389/fncir.2021.691314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406690PMC
August 2021

Development of a new method for assessing otolith function in mice using three-dimensional binocular analysis of the otolith-ocular reflex.

Sci Rep 2021 08 25;11(1):17191. Epub 2021 Aug 25.

Department of Otorhinolaryngology - Head and Neck Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

In the interaural direction, translational linear acceleration is loaded during lateral translational movement and gravitational acceleration is loaded during lateral tilting movement. These two types of acceleration induce eye movements via two kinds of otolith-ocular reflexes to compensate for movement and maintain clear vision: horizontal eye movement during translational movement, and torsional eye movement (torsion) during tilting movement. Although the two types of acceleration cannot be discriminated, the two otolith-ocular reflexes can distinguish them effectively. In the current study, we tested whether lateral-eyed mice exhibit both of these otolith-ocular reflexes. In addition, we propose a new index for assessing the otolith-ocular reflex in mice. During lateral translational movement, mice did not show appropriate horizontal eye movement, but exhibited unnecessary vertical torsion-like eye movement that compensated for the angle between the body axis and gravito-inertial acceleration (GIA; i.e., the sum of gravity and inertial force due to movement) by interpreting GIA as gravity. Using the new index (amplitude of vertical component of eye movement)/(angle between body axis and GIA), the mouse otolith-ocular reflex can be assessed without determining whether the otolith-ocular reflex is induced during translational movement or during tilting movement.
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http://dx.doi.org/10.1038/s41598-021-96596-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387381PMC
August 2021

Time-Course Changes in Bone Metabolism Markers and Density in Patients with Osteoporosis Treated with Romosozumab: A Multicenter Retrospective Study.

Yonsei Med J 2021 Sep;62(9):829-835

Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Purpose: In this multicenter retrospective observational study, we examined the early effects of romosozumab in patients with severe osteoporosis in terms of time-course changes in bone metabolism marker, improvement in bone density, and adverse effects.

Materials And Methods: Patients with severe osteoporosis were included. We investigated the progress of TRACP 5b and P1NP before and 1-2 months after the administration of romosozumab. We also investigated the bone density of lumbar spine, femoral neck, and the entire femur, measured by the DXA method, before and 5-7 months after the administration of romosozumab.

Results: A total of 70 patients (7 males and 63 females, age 75.0±3.6 years) participated in this study. Significant improvements in TRACP 5b and P1NP levels were observed before and 1-2 months after romosozumab administration. The average bone density of lumbar spine, femoral neck, and the entire femur were measured before and 5-7 months after romosozumab administration; and a significant increase only observed in the lumbar spine.

Conclusion: Consistent with the findings of previous clinical studies, romosozumab has both bone formation-enhancing and bone resorption effects (dual effect). In addition, romosozumab also demonstrated improvement in bone density from the early phase after the administration, though the result was only seen in the lumbar spine.
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http://dx.doi.org/10.3349/ymj.2021.62.9.829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382732PMC
September 2021

Real-world evaluation of second line chemotherapy for patients with advanced non-small cell lung cancer harboring preexisting interstitial lung disease.

Invest New Drugs 2021 Aug 20. Epub 2021 Aug 20.

Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara-city, Kanagawa, 252-0374, Japan.

Background: The optimal second and subsequent lines of chemotherapy for patients with non-small cell lung cancer (NSCLC) who have preexisting interstitial lung disease (ILD) are unclear. Hence, we examined the clinical efficacy and safety of second-line chemotherapy in such patients, including any exacerbation of preexisting ILD.

Methods: The medical records of patients with NSCLC and preexisting ILD who received both first- and second-line chemotherapy were retrospectively reviewed.

Results: Twenty-four patients with a median age of 71 years who were treated between April 2013 and March 2021 were included. The response rate after second-line chemotherapy with S-1 (n = 13), docetaxel (n = 8), pemetrexed (n = 2), or docetaxel plus ramucirumab (n = 1) was 12.5%, with a median progression-free survival (2nd line PFS) of 3.8 months. The overall survival from a start of first-line chemotherapy (1 line OS) and post-progression survival (PPS) post-first-line chemotherapy were 18.7 and 9.7 months, respectively. Spearman rank correlation and linear regression analyses showed that PPS was strongly correlated with 1st line OS (R = 0.85, P < 0.00001). Importantly, the 2nd line PFS was also significantly correlated with 1st line OS (R = 0.71, P = 0.0001). While second-line chemotherapy-related acute exacerbation of ILD was observed in 7 patients (29.2%), there were no treatment-related fatalities. Conslusions. Second-line chemotherapy has a strong positive impact on the OS of patients with NSCLC who have preexisting ILD. Given the findings of this study, second-line chemotherapy may be valuable in terms of prolonging long-term OS.
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http://dx.doi.org/10.1007/s10637-021-01162-xDOI Listing
August 2021

Comparison between intervertebral oblique lumbar interbody fusion and transforaminal lumbar interbody fusion: a multicenter study.

Sci Rep 2021 08 17;11(1):16673. Epub 2021 Aug 17.

Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

This study aimed to perform a comparative analysis of postoperative results between lumbar degenerative spondylolisthesis (LDS) treated with oblique lateral interbody fusion (OLIF) and transforaminal lumbar interbody fusion (TLIF) from the Chiba spine surgery registry database. Sixty-five patients who underwent single-level OLIF (O group) for LDS with ≥ 3 years' follow-up were retrospectively reviewed. The control group comprised 78 patients who underwent single-level TLIF (T group). The analyzed variables included global alignment, radiological parameters of fused segments, asymptomatic and symptomatic ASD incidence, clinical outcomes at 3 years postoperatively using the Japanese Orthopedic Association Back Pain Evaluation Questionnaire data, visual analogue scale scores for low back pain, lower extremity pain, and lower extremity numbness. There was no significant change in global alignment between the two groups. The rate of improvement in anterior intervertebral disc height was not significantly different between the groups at 1-month postoperatively. However, at the final evaluation, the anterior intervertebral disc height and incidence of asymptomatic ASD were significantly higher in the O group. There was no significant difference in symptomatic ASD, reoperation cases, or clinical results between groups. Thus, single-level OLIF can maintain the corrected disc height, but as it has no effect on global alignment, its benefit is limited.
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http://dx.doi.org/10.1038/s41598-021-95774-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371103PMC
August 2021

A case of lung adenocarcinoma with a novel CD74-ROS1 fusion variant identified by comprehensive genomic profiling that responded to crizotinib and entrectinib.

Thorac Cancer 2021 Sep 28;12(18):2504-2507. Epub 2021 Jul 28.

Division of Pulmonary Medicine, Department of Medicine, Keiyu Hospital, Yokohama, Japan.

ROS1 rearrangements are found in 1-2% of patients with non-small-cell lung cancer. The detection of the rearrangements is crucial since clinically effective molecular targeted drugs are available for them. We present a case of lung adenocarcinoma with a previously unknown ROS1-CD74 fusion variant, CD74 exon 3 fused to ROS1 exon 34, which was not detected by a conventional RT-PCR-based test for ROS1 fusion gene detection but identified by hybrid capture-based next-generation sequencing. This tumor responded to crizotinib initially and to entrectinib after relapse with brain metastasis, indicating the oncogenic activity of this novel fusion variant.
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http://dx.doi.org/10.1111/1759-7714.14093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447907PMC
September 2021

Comparison of post-operative three-dimensional and two-dimensional evaluation of component position for total knee arthroplasty.

Knee Surg Relat Res 2021 Jul 13;33(1):21. Epub 2021 Jul 13.

Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori Chuo-ku, Niigata City, Niigata, 951-8510, Japan.

Purpose: The purpose of this study was to evaluate the post-operative three-dimensional (3D) femoral and tibial component positions in total knee arthroplasty (TKA) by the same co-ordinates' system as for pre-operative planning and to compare it with a two-dimensional (2D) evaluation.

Materials And Methods: Sixty-five primary TKAs due to osteoarthritis were included. A computed tomography (CT) scan of the femur and tibia was obtained and pre-operative 3D planning was performed. Then, 3D and 2D post-operative evaluations of the component positions were performed. KneeCAS (LEXI, Inc., Tokyo, Japan), a lower-extremity alignment assessment system, was used for the 3D post-operative evaluation. Standard short-knee radiographs were used for the 2D post-operative evaluation. Differences between the pre-operative planning and post-operative coronal and sagittal alignment of components were investigated and compared with the results of the 3D and 2D evaluations.

Results: According to the 3D evaluation, the difference between the pre-operative planning and actual post-operative sagittal alignment of the femoral component and the coronal and sagittal alignments of the tibial component were 2.6° ± 1.8°, 2.2° ± 1.8° and 3.2° ± 2.4°, respectively. Using the 2D evaluation, they were 1.9° ± 1.5°, 1.3° ± 1.2° and 1.8° ± 1.4°, making the difference in 3D evaluation significantly higher (p = 0.013, = 0.003 and < 0.001). For the sagittal alignment of the femoral component and the coronal and sagittal alignment of the tibial component, the outlier (> ± 3°) ratio for the 3D evaluation was also significantly higher than that of the 2D evaluation (p < 0.001, = 0.009 and < 0.001).

Conclusions: The difference between the pre-operative planning and post-operative component alignment in the 3D evaluation is significantly higher than that of the 2D, even if the same cases have been evaluated. Two-dimensional evaluation may mask or underestimate the post-operative implant malposition. Three-dimensional evaluation using the same co-ordinates' system as for pre-operative planning is necessary to accurately evaluate the post-operative component position.
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http://dx.doi.org/10.1186/s43019-021-00106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278642PMC
July 2021

Association between the toe angle and bony factors in the transverse plane for osteoarthritic knees compared with healthy knees.

Biomed Mater Eng 2021 Jul 7. Epub 2021 Jul 7.

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.

Background: The association between the toe angle and bony rotational factors is critical to explain issues related to the onset and progression of knee osteoarthritis (OA).

Objective: The study aimed to clarify the association between the toe angle and each of the femoral and tibial transvers direction relative to gait direction, rotational knee alignment, and bony torsional deformity for the subjects with knee OA.

Methods: This study evaluated 58 knees in 24 healthy elderly (72 ± 5 years) and 34 varus knee OA (72 ± 6 years). A three-dimensional (3D) assessment system was used on 3D models and biplanar long-leg radiographs with the toe angle reflecting gait direction, applying a 3D-to-2D image registration technique. The main parameters on the transverse plane were: (1) toe angle, (2) transverse direction of the femur and tibia relative to the gait direction, (3) femoral neck anteversion, (4) condylar twist angle, (5) tibial torsion, and (6) rotational knee alignment.

Results: The alignment parameters, except for the tibial transverse direction, were different between healthy and osteoarthritic knees. In knee OA, the femoral neck anteversion - femoral transverse direction (p = 0.001), femoral transverse direction - tibial transverse direction (p < 0.001), and tibial transverse direction - toe angle (p < 0.001) were associated.

Conclusions: The osteoarthritic knees showed that the femoral neck anteversion was associated with the femoral transverse direction, which determined the tibial transverse direction by adjusting the rotational knee alignment, leading to the toe angle.
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http://dx.doi.org/10.3233/BME-211245DOI Listing
July 2021

Temporal maturation of neutralizing antibodies in COVID-19 convalescent individuals improves potency and breadth to circulating SARS-CoV-2 variants.

Immunity 2021 08 2;54(8):1841-1852.e4. Epub 2021 Jul 2.

National Institute of Infectious Diseases, Tokyo, 162-8640, Japan.

Antibody titers against SARS-CoV-2 slowly wane over time. Here, we examined how time affects antibody potency. To assess the impact of antibody maturation on durable neutralizing activity against original SARS-CoV-2 and emerging variants of concern (VOCs), we analyzed receptor binding domain (RBD)-specific IgG antibodies in convalescent plasma taken 1-10 months after SARS-CoV-2 infection. Longitudinal evaluation of total RBD IgG and neutralizing antibody revealed declining total antibody titers but improved neutralization potency per antibody to original SARS-CoV-2, indicative of antibody response maturation. Neutralization assays with authentic viruses revealed that early antibodies capable of neutralizing original SARS-CoV-2 had limited reactivity toward B.1.351 (501Y.V2) and P.1 (501Y.V3) variants. Antibodies from late convalescents exhibited increased neutralization potency to VOCs, suggesting persistence of cross-neutralizing antibodies in plasma. Thus, maturation of the antibody response to SARS-CoV-2 potentiates cross-neutralizing ability to circulating variants, suggesting that declining antibody titers may not be indicative of declining protection.
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http://dx.doi.org/10.1016/j.immuni.2021.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249673PMC
August 2021

Effect of Sitting Position vs. Supine Position With the Head Turned to the Affected Side on Benign Paroxysmal Positional Vertigo Fatigue.

Front Neurol 2021 17;12:705034. Epub 2021 Jun 17.

Department of Otorhinolaryngology - Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

In benign paroxysmal positional vertigo (BPPV), positional nystagmus becomes generally weaker when the Dix-Hallpike test is repeated. This phenomenon is termed BPPV fatigue. We previously reported that the effect of BPPV fatigue deteriorates over time (i.e., the positional nystagmus is observed again after maintaining a sitting head position). The aim of this study was to investigate whether the effect of BPPV fatigue attenuates after maintaining a supine position with the head turned to the affected side. Twenty patients with posterior-canal-type BPPV were assigned to two groups. Group A received Dix-Hallpike test, were returned to the sitting position (reverse Dix-Hallpike test) with a sitting head position for 10 min, and then received a second Dix-Hallpike test. Group B received Dix-Hallpike test, were kept in the supine position with the head turned to the affected side for 10 min, and then received reverse Dix-Hallpike test followed by the second Dix-Hallpike test. The maximum slow phase eye velocity (MSPEV) of positional nystagmus induced by the first, reverse, and second Dix-Hallpike test were analyzed. The ratio of MSPEV of the positional nystagmus induced by the second Dix-Hallpike test relative to the first Dix-Hallpike test was significantly smaller in group B than that in group A. There was no difference in the MSPEV of the positional nystagmus induced by the reverse Dix-Hallpike test between group A and B. The effect of BPPV fatigue is continued by maintaining a supine position with the head turned to the affected side, while the effect is weakened by maintaining a sitting head position. On the basis of the most widely accepted theory of the pathophysiology of BPPV fatigue, in which the particles become dispersed along the canal during head movement in the Dix-Hallpike test, we found an inconsistency whereby the dispersed otoconial debris return to a mass during the sitting position but do not return to a mass in the supine position with the head turned to the affected side. Future studies are required to determine the exact pathophysiology of BPPV fatigue. 2b.
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http://dx.doi.org/10.3389/fneur.2021.705034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247571PMC
June 2021

N-glycan structures of Wisteria floribunda agglutinin-positive Mac2 binding protein in the serum of patients with liver fibrosis†.

Glycobiology 2021 Jun 29. Epub 2021 Jun 29.

Glycoscience & Glycotechnology Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science & Technology, Tsukuba, Ibaraki 305-8568, Japan.

The extent of liver fibrosis predicts prognosis and is important for determining treatment strategies for chronic hepatitis. During the fibrosis progression, serum levels of Mac2 binding protein (M2BP) increase and the N-glycan structure changes to enable binding to Wisteria floribunda agglutinin (WFA) lectin. As a novel diagnostic marker, glycosylation isomer of M2BP (M2BPGi) has been developed. However, its glycan structures recognized by WFA are unclear. In this study, we analyzed site-specific N-glycan structures of serum M2BP using Glyco-RIDGE (Glycan heterogeneity-based Relational IDentification of Glycopeptide signals on Elution profile) method. We evaluated five sample types: 1) M2BP immunoprecipitated from normal healthy sera (NHS-IP(+)), 2) M2BP immunoprecipitated from sera of patients with liver cirrhosis (stage 4; F4-IP(+)), 3) M2BP captured with WFA from serum of patients with liver cirrhosis (stage 4; F4-WFA(+)), 4) recombinant M2BP produced by HEK293 cells (rM2BP), and 5) WFA-captured rM2BP (rM2BP-WFA(+)). In NHS-IP(+) M2BP, bi-antennary N-glycan was the main structure, and LacNAc extended to its branches. In F4-IP(+) M2BP, many branched structures, including tri-antennary and tetra-antennary N-glycans, were found. F4-WFA(+) showed a remarkable increase in branched structures relative to the quantity before enrichment. In recombinant M2BP, both no sialylated-LacdiNAc and -branched LacNAc structures were emerged. The LacdiNAc structure was not found in serum M2BP. Glycosidase-assisted HISCL assays suggest that, reactivity with WFA of both serum and recombinant M2BP depends on unsialylated and branched LacNAc, and in part of recombinant, depends on LacdiNAc. On M2BPGi, the highly branched LacNAc, probably dense cluster of LacNAc, would be recognized by WFA.
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http://dx.doi.org/10.1093/glycob/cwab060DOI Listing
June 2021

Molecular recognition of a single-chain Fv antibody specific for GA-pyridine, an advanced glycation end-product (AGE), elucidated using biophysical techniques and synthetic antigen analogues.

J Biochem 2021 Oct;170(3):379-387

Department of Analytical and Biophysical Chemistry, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.

Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by non-enzymatic reaction between reducing-sugar and Arg/Lys in proteins and are involved in various diabetic complications. GA-pyridine is derived from glycolaldehyde and is one of the most cytotoxic AGEs. Here, we established a single-chain Fv (scFv) antibody against GA-pyridine, 73MuL9-scFv, and examined the details of its specificity and antigen recognition by using various techniques involving biophysics, chemical biology and structural biology. We also synthesized several compounds that differ slightly in regard to the position and number of GA-pyridine substituent groups, and revealed that GA-pyridine was specifically bound to 73MuL9-scFv. Thermodynamic analysis revealed that the association of GA-pyridine to 73MuL9-scFv was an exothermic and enthalpy driven reaction, and thus that the antigen recognition involved multiple specific interactions. Crystallographic analysis of the Fv fragment of 73MuL9-scFv revealed that several CH-π and hydrogen bond interactions took place between the Fv-fragment and GA-pyridine, which was consistent with the results of thermodynamic analysis. Further studies using 73MuL9-scFv as a tool to clarify the relevance of GA-pyridine to diabetic complications are warranted.
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http://dx.doi.org/10.1093/jb/mvab056DOI Listing
October 2021

Real-world clinical outcomes of sofosbuvir and velpatasvir treatment in HCV genotype 1- and 2-infected patients with decompensated cirrhosis: A nationwide multicenter study by the Japanese Red Cross Liver Study Group.

J Med Virol 2021 Nov 3;93(11):6247-6256. Epub 2021 Jul 3.

Department of Gastroenterology and Hepatology, Japanese Red Cross Musashino Hospital, Tokyo, Japan.

The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with sofosbuvir (SOF) and velpatasvir (VEL) were assessed in hepatitis C virus (HCV) genotype 1- and 2-infected patients with decompensated cirrhosis. A total of 65 patients with HCV-related decompensated cirrhosis (Child-Pugh score of 7 points or more) who were treated with the SOF/VEL regimen were enrolled. The sustained virological response (SVR) rate and safety profile were analyzed. SVR was defined as undetectable serum HCV RNA at 12 weeks after the end of treatment (SVR12). The percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 81.2% (95% confidence interval [CI], 69.5-89.9) (52/64), 98.4% (95% CI, 91.2-100.0) (60/61), and 98.5% (95% CI, 91.7-100.0) (64/65), respectively. The overall SVR rate was 92.3% (95% CI, 83.0-97.5) (60/65). Albumin-bilirubin (ALBI) scores decreased during and after treatment (p < 0.001), and there were significant differences between baseline and end of treatment and between baseline and SVR12. Subgroup analyses showed no significant differences in SVR rates according to patient age, sex, HCV genotype (subtype), Child-Pugh classification, modified ALBI grade, presence of ascites, presence of hepatic coma, or history of hepatocellular carcinoma. In all subpopulations, the SVR rates were higher than 80%. There were no severe adverse events associated with the treatment. The SOF/VEL regimen showed good virological efficacy and acceptable safety even in patients with HCV-related decompensated cirrhosis.
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http://dx.doi.org/10.1002/jmv.27157DOI Listing
November 2021

Comparison of Kinematics and Contact Mechanics in Normal Knee and Total Knee Replacements: A Computational Investigation.

Ann Biomed Eng 2021 Sep 17;49(9):2491-2502. Epub 2021 Jun 17.

Department of Mechanical Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.

An objective of total knee replacement (TKR) is to restore the mechanical function of a normal knee. Joint kinematics and contact mechanics performance are two of the primary indices that indicate the success of TKR devices. The aim of this study was to compare the kinematics and contact mechanics of TKR and normal knee joints. An experimentally evaluated finite-element (FE) knee model was developed and used to investigate the performance of four TKR designs (fixed cruciate-retaining (CR), mobile CR, posterior-stabilized (PS), medial pivot design (MP)) and the normal knee joint during a gait cycle. The predicted kinematic results showed that the MP design presented similar kinematics to those of the normal knee joint and did not demonstrate paradoxical motion of the femur. A considerably larger contact area and lower contact pressure were found on the normal knee joint (1315 mm, and 14.8 MPa, respectively) than on the TKRs, which was consistent with the previous in-vivo fluoroscopic investigation. The mobile CR and PS designs exhibited the smallest and greatest contact pressures of the four TKR designs, respectively. The results of the present study help to understand the kinematics and contact mechanics in the TKR during the gait cycle, and provide comprehensive information about the performance of the normal knee joint.
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http://dx.doi.org/10.1007/s10439-021-02812-0DOI Listing
September 2021

Improvements in Intractable Lumbar and LowerExtremity Symptoms after Systemic Administration of Tocilizumab, an Anti-interleukin-6 Receptor Antibody.

Asian Spine J 2021 May 21. Epub 2021 May 21.

Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Study Design: Prospective cohort study (open-label, single-arm, and non-blinded).

Purpose: This study aims to determine the effects of systemic administration of tocilizumab, an anti-interleukin-6 (IL-6) receptor antibody on refractory low back pain and leg symptoms.

Overview Of Literature: IL-6 overexpression is associated with neuropathic pain pathogenesis, which is potentially followed by chronic low back pain, including leg pain and numbness. This finding suggest that inhibition of IL-6 at the site of pain or in the transmission pathway could provide novel therapeutic targets for chronic low back pain.

Methods: This prospective, single-arm study included 11 patients (eight men; mean age, 62.7 years) with ≥3-months' chronic pain history due to lumbar disease. Subcutaneous TCZ injections were administered twice, at a 2-week interval. We evaluated low back pain, leg pain, and leg numbness using numeric rating scales and the Oswestry Disability Index (ODI; baseline and 6 months postinjection); serum IL-6 and tumor necrosis factor-α levels (baseline and 1 month postinjection); and clinical adverse events.

Results: Intractable symptoms reduced after TCZ administration. Low back pain improved for 6 months. Improvements in leg pain and numbness peaked at 4 and 1 month, respectively. Improvements in ODI were significant at 1 month and peaked at 4 months. Serum IL-6 was increased at 1 month. IL-6 responders (i.e., patients with IL-6 increases >10 pg/mL) showed particularly significant improvements in leg pain at 2 weeks, 1 month, and 2 months compared with nonresponders. We observed no apparent adverse events.

Conclusions: Systemic TCZ administration improved symptoms effectively for 6 months, with peak improvements at 1-4 months and no adverse events. Changing serum IL-6 levels correlated with leg pain improvements; further studies are warranted to elucidate the mechanistic connections between lumbar disorders and inflammatory cytokines.
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http://dx.doi.org/10.31616/asj.2020.0283DOI Listing
May 2021

Usefulness of Simultaneous Magnetic Resonance Neurography and Apparent T2 Mapping for the Diagnosis of Cervical Radiculopathy.

Asian Spine J 2021 May 20. Epub 2021 May 20.

Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Study Design: Retrospective observational study.

Purpose: We investigated the correlation between T2 relaxation times and clinical symptoms in patients with cervical radiculopathy caused by cervical disk herniation.

Overview Of Literature: There are currently no imaging modalities that can assess the affected cervical nerve roots quantitatively.

Methods: A total of 14 patients with unilateral radicular symptoms and five healthy subjects were subjected to simultaneous apparent T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement signaling (SHINKEI-Quant) using a 3-Tesla magnetic resonance imaging. The Visual Analog Scale (VAS) score for neck pain and upper arm pain was used to evaluate clinical symptoms. T2 relaxation times of the cervical dorsal root ganglia of the brachial plexus were measured bilaterally from C4 to C8 in patients with radicular symptoms and from C5 to C8 in healthy controls. The T2 ratio was calculated as the affected side to unaffected side.

Results: When comparing nerve roots bilaterally at each spinal level, no significant differences in T2 relaxation times were found between patients and healthy subjects. However, T2 relaxation times of nerve roots in the patients with unilateral radicular symptoms were significantly prolonged on the involved side compared with the uninvolved side (p<0.05). The VAS score for upper arm pain was not significantly correlated with the T2 relaxation times, but was positively correlated with the T2 ratio.

Conclusions: In patients with cervical radiculopathy, the SHINKEI-Quant technique can be used to quantitatively evaluate the compressed cervical nerve roots. The VAS score for upper arm pain was positively correlated with the T2 ratio. This suggests that the SHINKEI-Quant is a potential tool for the diagnosis of cervical nerve entrapment.
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http://dx.doi.org/10.31616/asj.2020.0668DOI Listing
May 2021

Influence of posterior tibial slope on three-dimensional femorotibial alignment under weight-bearing conditions in healthy Japanese elderly people.

Biomed Mater Eng 2021 ;32(3):183-194

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.

Background: Assessment of three-dimensional (3D) femorotibial alignment is essential for successful knee osteoarthritis treatment in the elderly. The complex morphology of the posterior tibial slope (PTS) might have an influence on sagittal and rotational alignment and the positional relationship between the femur and tibia in the anterior-posterior (AP) direction under weight-bearing conditions.

Objective: This study aimed to clarify the association between the PTS and 3D femorotibial alignment under weight-bearing conditions in healthy Japanese elderly individuals.

Methods: We investigated the 3D femorotibial alignment of 110 lower extremities of 55 healthy individuals (26 women, 29 men, mean age: 70 ± 6 years). Using our previously reported 3D-to-2D image registration technique, we evaluated the 3D hip-knee-ankle angle (3DHKA) in the sagittal plane, rotational alignment, and the distance between the femoral and tibial origins in the AP direction (tibial AP position) as femorotibial alignment parameters under weight-bearing conditions. We assessed the medial and lateral PTS and their angular difference (PTS difference) as PTS parameters. Stepwise multiple linear regression analysis was performed using PTS parameters and other possible confounders (age, sex, height, and weight) as the independent variables and femorotibial alignment parameters as the dependent variable.

Results: Weight (𝛽 = 0.393, p < 0.001) and lateral PTS (𝛽 = 0.298, p < 0.001) were the predictors associated with 3DHKA in the sagittal plane. Lateral PTS (𝛽 = 0.304, p = 0.001) was the only predictor associated with the tibial AP position. Sex (𝛽 = -0.282, p = 0.002) and PTS difference (𝛽 = -0.231, p = 0.012) were associated with rotational alignment.

Conclusions: We found that a steeper lateral PTS resulted in a more flexed knee and anterior tibia. The PTS difference was positively correlated with tibial external rotation. Our data could be used as the standard reference for realignment surgery to ensure PTS is appropriately maintained.
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http://dx.doi.org/10.3233/BME-201209DOI Listing
August 2021

An increase in normetanephrine in hair follicles of acne lesions through the sympatho-adrenal medullary system in acne patients with anxiety.

J Dermatol 2021 Aug 7;48(8):1281-1285. Epub 2021 May 7.

Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.

Acne vulgaris, a chronic inflammatory skin disease, has been associated with not only sebaceous gland dysfunction but also various endogenous and exogenous stresses. Since sebaceous glands are under neuroendocrine control, including the hypothalamic-pituitary-adrenal axis and neuro-autocrine mechanisms, it remains unclear how psychological stress relates to the pathogenesis of acne. In this study, we investigated the relationship between psychological stress and catecholamine in acne lesions from 18 patients with mild or moderate acne. The State-Trait Anxiety Inventory (STAI) revealed that all patients were anxious, with six having low anxiety and 12 high anxiety. Salivary α-amylase activity (sAA), which is regulated by the sympatho-adrenal medullary (SAM) system, positively correlated with the STAI State Anxiety scores (STAI-S) and was significantly detectable in acne patients with high rather than low anxiety. In addition, the level of normetanephrine, but not metanephrine, both of which are catecholamine metabolites, in hair follicles of acne lesions also positively correlated with the STAI-S. Furthermore, the normetanephrine level was higher in patients with high rather than low anxiety, whereas there was no change in metanephrine in the hair follicles of the acne lesions. Moreover, neither the sAA nor metanephrine and normetanephrine in the acne lesions was related to acne severity in the patients. Thus, these results provide novel evidence that a SAM system-associated increase of normetanephrine level in hair follicles is involved in the acne pathology of patients with anxiety.
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http://dx.doi.org/10.1111/1346-8138.15935DOI Listing
August 2021

Application of Nitrate, Ammonium, or Urea Changes the Concentrations of Ureides, Urea, Amino Acids and Other Metabolites in Xylem Sap and in the Organs of Soybean Plants ( (L.) Merr.).

Int J Mol Sci 2021 Apr 27;22(9). Epub 2021 Apr 27.

Graduate School of Science and Technology, Niigata University, Niigata 950-2181, Japan.

Soybean ( (L.) Merr.) plants form root nodules and fix atmospheric dinitrogen, while also utilizing the combined nitrogen absorbed from roots. In this study, nodulated soybean plants were supplied with 5 mM N nitrate, ammonium, or urea for 3 days, and the changes in metabolite concentrations in the xylem sap and each organ were analyzed. The ureide concentration in the xylem sap was the highest in the control plants that were supplied with an N-free nutrient solution, but nitrate and asparagine were the principal compounds in the xylem sap with nitrate treatment. The metabolite concentrations in both the xylem sap and each organ were similar between the ammonium and urea treatments. Considerable amounts of urea were present in the xylem sap and all the organs among all the treatments. Positive correlations were observed between the ureides and urea concentrations in the xylem sap as well as in the roots and leaves, although no correlations were observed between the urea and arginine concentrations, suggesting that urea may have originated from ureide degradation in soybean plants, possibly in the roots. This is the first finding of the possibility of ureide degradation to urea in the underground organs of soybean plants.
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http://dx.doi.org/10.3390/ijms22094573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123890PMC
April 2021

Three-dimensional morphology of the distal femur based on surgical epicondylar axis in the normal elderly population.

Knee 2021 Jun 23;30:125-133. Epub 2021 Apr 23.

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.

Background: We aimed to analyze the surface morphology of the distal femur in three dimensions for the healthy elderly, based on the concept that the surgical epicondylar axis (SEA) is a better surrogate for the flexion-extension axis of the knee joint.

Methods: We studied 77 healthy elderly volunteers (40 males and 37 females; age, 68 ± 6 years). The medial and lateral contact lines were calculated three-dimensionally, using the highest points of the medial and lateral condyles in 201 cross-sectional planes around the SEA (every 1°, -60° (hyperextension) to 140° (flexion)). A piecewise fitting function consisting of two linear segments was applied to detect the inflection point of the constant radii in the sagittal plane. The main assessment parameters were knee flexion angle at the inflection point of the radius (inflection angle), mean radius from 0° to the inflection angle (constant radius), and coronal tilt angle of the contact line.

Results: The inflection angles, constant radii, and coronal tilt angles were 78.2 ± 8.6°, 26.1 ± 2.3 mm, and -0.6 ± 3.2° and 65.6 ± 9.2°, 23.9 ± 2.2 mm, and 6.2 ± 3.2° in the medial and lateral condyles, respectively (all, P < 0.001). The coronal alignment was 88.7 ± 2.2°.

Conclusions: The medial and lateral femoral condyles showed asymmetrical morphologies with the almost 'constant' radius of sagittal curvature from 0° to around 80° and 65° of knee flexion, respectively.
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http://dx.doi.org/10.1016/j.knee.2021.03.022DOI Listing
June 2021

Platinum-doublet chemotherapy as second-line treatment for relapsed patients with small-cell lung cancer: A systematic review and meta-analysis.

Lung Cancer 2021 06 19;156:59-67. Epub 2021 Apr 19.

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Objective: Optimal second-line chemotherapy for patients with relapsed small-cell lung cancer remains debatable. In addition to topotecan or amrubicin monotherapy, re-challenge with first-line platinum-doublets have been commonly used. In this study, we investigated whether platinum-doublets are suitable as second-line treatment for relapsed small-cell lung cancer.

Materials And Methods: Studies that enrolled relapsed small-cell lung cancer and compared platinum-doublets with non-platinum-based regimens for second-line treatment were identified using PubMed and EMBASE. A meta-analysis was conducted to calculate the relative risk of objective response rate and disease control rate of the second-line chemotherapy. Subgroup analyses were conducted to focus on comparison with standard second-line regimens and sensitive relapse. Progression-free and overall survival, and adverse events were systematically reviewed.

Results: Ten studies published between 2011 and 2020 were included in our analysis with a total of 1222 patients: 438 treated with platinum-doublets and 784 with non-platinum-based regimens. The objective response rates for second-line platinum-doublet and non-platinum regimens were 47.3 % [95 % CI: 40.5-54.0] and 31.5 % [95 % CI: 22.2-40.8], respectively. Patients treated with platinum-doublets had a significantly higher objective response rate than patients with non-platinum-based regimens (RR [95 % CI]: 1.527 [1.100-2.121], p = 0.011), as well as disease control rate (RR [95 % CI]: 1.152 [1.052-1.262], p = 0.002). In a subgroup analysis comparing platinum-doublets with topotecan or amrubicin, patients treated with platinum-doublets had significantly higher objective response rate and disease control rate (RR [95 % CI]: 1.663 [1.055-2.619], p = 0.028 and 1.170 [1.021-1.340], p = 0.023 respectively). Progression-free and overall survival appeared consistent with the tumor responses. Adverse events associated with platinum-doublets appeared acceptable compared with the monotherapies.

Conclusion: Platinum-doublet chemotherapy as second-line treatment for patients with relapsed small-cell lung cancer can be considered as a reasonable option in comparison with non-platinum regimens.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.013DOI Listing
June 2021

Effects of Nintendo Ring Fit Adventure Exergame on Pain and Psychological Factors in Patients with Chronic Low Back Pain.

Games Health J 2021 Jun 22;10(3):158-164. Epub 2021 Apr 22.

Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

In recent years, there has been an increase in research on the therapeutic effects of exergaming, but there have been few studies on these types of interventions for chronic low back pain. In this study, we hypothesized that the Nintendo Ring Fit Adventure (RFA) exergame would be effective for patients with chronic low back pain, and we conducted a randomized prospective longitudinal study. Patients with chronic low back pain were included in this study. Twenty randomly selected patients (9 males and 11 females, mean age 49.3 years) were included in the RFA group, and RFA exergaming was performed once a week for 40 minutes for 8 weeks. Twenty patients (12 males and 8 females, mean age 55.60 years) served as the control group and received oral treatment for 8 weeks. Pain and psychological scores (pain self-efficacy, pain catastrophizing, and kinesiophobia) were measured and analyzed before and after 8 weeks of treatment in both groups. In the RFA group, low back pain, buttock pain, and pain self-efficacy were significantly improved after 8 weeks of RFA exergaming, but there was no significant improvement in lower limb numbness, pain catastrophizing, or kinesiophobia. In the control group, no significant improvement was observed after 8 weeks of oral treatment. RFA exergaming increased pain self-efficacy and reduced pain in patients with chronic low back pain. Future treatment protocols should be developed to improve pain self-efficacy. 2894, School of Medicine, Chiba University.
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http://dx.doi.org/10.1089/g4h.2020.0180DOI Listing
June 2021

Phosphorylation of MYL12 by Myosin Light Chain Kinase Regulates Cellular Shape Changes in Cochlear Hair Cells.

J Assoc Res Otolaryngol 2021 07 20;22(4):425-441. Epub 2021 Apr 20.

Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

The organ of Corti is an auditory organ located in the cochlea, comprising hair cells (HCs) and other supporting cells. Cellular shape changes of HCs are important for the development of auditory epithelia and hearing function. It was previously observed that HCs and inner sulcus cells (ISCs) demonstrate cellular shape changes similar to the apical constriction of the neural epithelia. Apical constriction is induced via actomyosin cable contraction in the apical junctional complex and necessary for the physiological function of the epithelium. Actomyosin cable contraction is mainly regulated by myosin regulatory light chain (MRLC) phosphorylation by myosin light chain kinase (MLCK). However, MRLC and MLCK isoforms expressed in HCs and ISCs are unknown. Hence, we investigated the expression patterns and roles of MRLCs and MLCKs in HCs. Droplet digital PCR revealed that HCs expressed MYL12A/B and MYL9, which are non-muscle MRLC and smooth muscle MLCK (smMLCK), respectively. Immunofluorescence staining throughout the organ of Corti demonstrated that only MYL12 was expressed in the apical portion of HCs, whereas MYL12 and MYL9 were expressed on ISCs. In addition, purified MYL12B was phosphorylated by smMLCK in vitro, and the harvested HCs contained phosphorylated MYL12. Furthermore, accompanied by the expansion of the cell area of outer HCs, MYL12 phosphorylation was reduced by ML-7, which is an inhibitor of smMLCK. In conclusion, MYL12 phosphorylation by smMLCK contributed to the apical constriction-like cellular shape change of HCs possibly relating to the development of auditory epithelia and hearing function.
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http://dx.doi.org/10.1007/s10162-021-00796-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329122PMC
July 2021
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