Publications by authors named "Satoru Takahashi"

874 Publications

Efficacy of mirabegron, a β -adrenoreceptor agonist, in Japanese women with overactive bladder and either urgency urinary incontinence or mixed urinary incontinence: Post-hoc analysis of pooled data from two randomized, placebo-controlled, double-blind studies.

Int J Urol 2021 Oct 4. Epub 2021 Oct 4.

Medical Affairs, Astellas Pharma Inc., Japan.

Objective: To confirm if mirabegron 50 mg shows efficacy in women with overactive bladder and either urgency urinary incontinence or mixed urinary incontinence versus placebo.

Methods: Post-hoc analyses were carried out using pooled data from a Japanese phase IIb and a phase III study. The primary efficacy end-point was baseline to end-of-treatment change in the mean number of micturitions/24 h. The secondary end-points were changes in the mean voided volume/micturition, mean number of urgency and incontinence episodes/24 h, and mean number of nocturia episodes/night. Other end-points were quality of life and incontinence normalization rates.

Results: Women with urgency urinary incontinence (placebo n  = 204, mirabegron n = 214) and mixed urinary incontinence (placebo n = 122, mirabegron n = 139) were included. Change in mean micturitions/24 h at end-of-treatment for mirabegron was statistically significant versus placebo in both populations; the effect size increased over time. For all secondary end-points, median changes for mirabegron were statistically significant versus placebo at end-of-treatment, except for nocturia for the urgency urinary incontinence population and urgency for the mixed urinary incontinence population. Mirabegron showed larger improvements versus placebo in all quality-of-life domains, except for general health perception in the urgency urinary incontinence population. Incontinence normalization rates for mirabegron were 47.2% and 49.6% in the urgency urinary incontinence and mixed urinary incontinence populations, respectively, versus 42.6% and 39.3% for placebo.

Conclusions: Mirabegron 50 mg significantly improved key overactive bladder symptoms versus placebo in women with urgency urinary incontinence, and it also improved most overactive bladder symptoms, including micturition frequency, in patients with mixed urinary incontinence. These findings support the benefits of using mirabegron in the female overactive bladder wet population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/iju.14700DOI Listing
October 2021

Tunable Synchronicity of Molecular Valence Tautomerism with Macroscopic Solid-Liquid Transition by Molecular Lattice Engineering.

Chemistry 2021 Sep 29. Epub 2021 Sep 29.

Department of Applied Chemistry Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga Bunkyo-ku, Tokyo, 112-8551, Japan.

The combination of a cobalt-dioxolene core that exhibits valence tautomerism (VT) with pyridine-3,5-dicarboxylic acid functionalized with chains bearing two, four, or six oxyethylene units led to new complexes ConEGEspy (n = 2, 4, and 6). These complexes commonly form violet crystals of the low-spin (ls)-[Co (nEGEspy) (3,6-DTBSQ)(3,6-DTBCat)] (ls-[Co ], 3,6-DTBSQ = 3,6-di-tert-butyl semiquinonato, 3,6-DTBCat = 3,6-di-tert-butyl catecholato). Interestingly, violet crystals of Co2EGEspy in the ls-[Co ] transitioned into a green liquid, accompanied by an almost complete VT shift (94 %) to the high-spin (hs)-[Co (nEGEspy) (3,6-DTBSQ) ] (hs-[Co ]) upon melting. In contrast, violet crystals of Co4EGEspy and Co6EGEspy in the ls-[Co ] exhibited partial VT (33 %) and only a 9.3 % VT shift after melting, respectively. These data demonstrate the tunability of the synchronicity of the molecular VT and macroscopic solid-liquid transitions by optimizing the tethered chains, thus establishing a new strategy for coupling bistable molecules with the macroscopic world.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/chem.202103090DOI Listing
September 2021

Guidelines for Infection Control in the Urological Field, including Urinary Tract Management (revised second edition).

Int J Urol 2021 Sep 3. Epub 2021 Sep 3.

Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan.

The Committee for the Development of Guidelines for Infection Control in the Urological Field, including Urinary Tract Management of the Japanese Urological Association, together with its systematic review team and external reviewers, have prepared a set of practice guidelines, an abridged version of which is published herein. These guidelines cover the following topics: (i) foundations of infection control, standard precautions, route-specific precautions, and occupational infection control (including vaccines); (ii) the relationship between urologists and infection control; (iii) infection control in urological wards and outpatient clinics; (iv) response to hepatitis B virus reactivation; (v) infection control in urological procedures and examinations; (vi) prevention of infections occurring in conjunction with medical procedures and examinations; (vii) responses to urinary tract tuberculosis and bacillus Calmette-Guérin; (viii) aseptic handling, cleaning, disinfection, and sterilization of urinary tract endoscopes (principles of endoscope manipulation, endoscope lumen cleaning, and disinfection); (ix) infection control in the operating room (principles of hand washing, preoperative rubbing methods, etc.); (x) prevention of needlestick and blood/bodily fluid exposure and response to accidental exposure; (xi) urinary catheter-associated urinary tract infection and purple urinary bag syndrome; and (xii) urinary catheter-associated urinary tract infections in conjunction with home care. In addressing these topics, the relevant medical literature was searched to the extent possible, and content was prepared for the purpose of providing useful information for clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/iju.14684DOI Listing
September 2021

Author Correction: Study of mouse behavior in different gravity environments.

Sci Rep 2021 Aug 27;11(1):17563. Epub 2021 Aug 27.

Mouse Epigenetics Project, ISS/Kibo Experiment, Japan Aerospace Exploration Agency, Tsukuba, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-96312-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397713PMC
August 2021

Adipsin-Dependent Secretion of Hepatocyte Growth Factor Regulates the Adipocyte-Cancer Stem Cell Interaction.

Cancers (Basel) 2021 Aug 23;13(16). Epub 2021 Aug 23.

Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan.

Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13164238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393397PMC
August 2021

Laparoscopic sacrocolpopexy for pelvic organ prolapse: Comparison of standard versus tacker combination method.

Int J Urol 2021 Aug 24. Epub 2021 Aug 24.

Department of Urology, Nihon University School of Medicine, Tokyo, Japan.

Objective: To compare the surgical outcomes of laparoscopic sacrocolpopexy for pelvic organ prolapse between a group in which only sutures were used (standard method), and a group in which a combination of tackers and sutures were used (tacker combination method).

Methods: A total of 77 patients who underwent laparoscopic sacrocolpopexys from June 2016 to October 2019 were divided into a suture group (36 patients) and a suture + tacker group (41 patients). We retrospectively compared operation time, amount of blood loss, postoperative length of hospital stay, incidence of perioperative complications and anatomical cure rate 1 year after surgery. Lower urinary tract symptoms were evaluated using symptom questionnaires and objective parameters.

Results: Operation time in the suture + tacker group was shorter (104.9 ± 27.0 vs 147.5 ± 33.7 min; P < 0.0001). The incidence of perioperative complications in the suture group and the suture + tacker group was 2.8% and 2.4%, respectively (P = 0.9409). Anatomical cure rates at 1 year after surgery were 94.4% and 100%, respectively (P = 0.2153). Both groups showed significant improvement after 1 year for International Prostate Symptom Score total and quality of life score, Overactive Bladder Symptom Score total score, voided volume, maximum urinary flow rate and post-void residual. [Corrections added on 7 September 2021 after first online publication: the first two P-values have been updated.] CONCLUSIONS: The combined use of sutures and tackers in laparoscopic sacrocolpopexy simplifies the procedure and translates into shorter operation time. Surgical outcomes at 1 year and improvement of lower urinary tract symptoms are similar regardless of the technique.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/iju.14676DOI Listing
August 2021

Dosimetric evaluation of ovaries and pelvic bones associated with clinical outcomes in patients receiving total body irradiation with ovarian shielding.

J Radiat Res 2021 Sep;62(5):918-925

Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 350-8550, Japan.

Total body irradiation (TBI) with ovarian shielding is expected to preserve fertility among hematopoietic stem cell transplant (HSCT) patients with myeloablative TBI-based regimens. However, the radiation dose to the ovaries that preserves ovarian function in TBI remains poorly understood. Furthermore, it is uncertain whether the dose to the shielded organs is associated with relapse risk. Here, we retrospectively evaluated the relationship between fertility and the dose to the ovaries, and between relapse risk and the dose to the pelvic bones. A total of 20 patients (median age, 23 years) with standard-risk hematologic diseases were included. Median follow-up duration was 31.9 months. The TBI prescribed dose was 12 Gy in six fractions for three days. Patients' ovaries were shielded with cylinder-type lead blocks. The dose-volume parameters (D98% and Dmean) in the ovaries and the pelvic bones were extracted from the dose-volume histogram (DVH). The mean ovary Dmean for all patients was 2.4 Gy, and 18 patients recovered menstruation (90%). The mean ovary Dmean for patients with menstrual recovery and without recovery were 2.4 Gy and 2.4 Gy, respectively, with no significant difference (P = 0.998). Hematological relapse was observed in five patients. The mean pelvis Dmean and pelvis D98% for relapse and non-relapse patients were 11.6 Gy and 11.7 Gy and 5.6 Gy and 5.3 Gy, respectively. Both parameters showed no significant difference (P = 0.827, 0.807). In conclusion, TBI with ovarian shielding reduced the radiation dose to the ovaries to 2.4 Gy, and preserved fertility without increasing the risk of relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jrr/rrab066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438484PMC
September 2021

Prognostic significance of the albumin-to-globulin ratio for advanced urothelial carcinoma treated with pembrolizumab: a multicenter retrospective study.

Sci Rep 2021 08 2;11(1):15623. Epub 2021 Aug 2.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Although the albumin-to-globulin ratio (AGR) is a promising biomarker, no study has investigated its prognostic significance for advanced urothelial carcinoma (UC). This study conformed to the REporting recommendations for tumor MARKer prognostic studies (REMARK) criteria. We retrospectively reviewed 176 patients with advanced UC treated with pembrolizumab between 2018 and 2020. We evaluated the associations between pretreatment clinicopathological variables, including the AGR and performance status (PS), with progression-free survival, cancer-specific survival, and overall survival. The Cox proportional hazards model was used for univariate and multivariable analyses. The AGR was dichotomized as < 0.95 and ≥ 0.95 based on receiver operating characteristic curve analysis. After excluding 26 cases with missing data from the total of 176 cases, 109 (73%) patients experienced disease progression, 75 (50%) died from UC, and 6 (4%) died of other causes (median survival = 12 months). Multivariate analyses identified PS ≥ 2 and pretreatment AGR < 0.95 as independent poor prognostic factors for all endpoints. Furthermore, a prognostic risk model incorporating these two variables achieved a relatively high concordance index for all endpoints. This is the first report to evaluate the significance of AGR in advanced UC. Pretreatment AGR < 0.95 may serve as a prognostic marker for advanced UC treated with pembrolizumab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-95061-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329063PMC
August 2021

Differential Involvement of Programmed Cell Death Ligands in Skin Immune Responses.

J Invest Dermatol 2021 Jul 24. Epub 2021 Jul 24.

Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address:

PD-1 is an immunoregulatory receptor that can bind PD-L1 or PD-L2 expressed on stimulated antigen-presenting cells. In this study, isolated antigen-presenting cells (macrophages and dendritic cells) were cultured with IFN-γ, IL-4, or IL-17A, and the expression of PD-L1 and PD-L2 was compared by flow cytometry. Strong upregulation of PD-L1 expression was observed on IFN-γ stimulation of both antigen-presenting cells as well as in response to IL-17A stimulation of macrophages compared with the expression in unstimulated controls. In contrast, only stimulation with IL-4 could upregulate PD-L2 expression on both antigen-presenting cells. Therefore, experiments were performed in murine models, including DNFB-induced contact hypersensitivity, calcipotriol-induced atopic dermatitis-like skin inflammation, and imiquimod-induced psoriasis-like dermatitis models, to trigger IFN-γ‒mediated T helper type (Th)1-, IL-4‒mediated Th2-, and IL-17A‒mediated Th17-type responses, respectively. In both Th1- and Th17-type immunity models, changes in ear thickness were more severe in Pd-l1‒deficient mice than in wild-type or Pd-l2‒deficient mice. In the Th2-type immunity model, changes in thickness in Pd-l2‒deficient mice were more severe than that in wild-type or Pd-l1‒deficient mice. Collectively, PD-L1 has predominant roles in Th1 and Th17 type immunity, whereas PD-L2 is involved in Th2-type immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2021.06.026DOI Listing
July 2021

Anti-Allergic Drug Suppressed Pancreatic Carcinogenesis via Down-Regulation of Cellular Proliferation.

Int J Mol Sci 2021 Jul 12;22(14). Epub 2021 Jul 12.

Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.

Pancreatic cancer is a fatal disease, and thus its chemoprevention is an important issue. Based on the recent report that patients with allergic diseases have a low risk for pancreatic cancer, we examined the potential chemopreventive effect of anti-allergic agents using a hamster pancreatic carcinogenesis model. Among the three anti-allergic drugs administered, montelukast showed a tendency to suppress the incidence of pancreatic cancer. Further animal study revealed a significantly decreased incidence of pancreatic cancer in the high-dose montelukast group compared with controls. The development of the pancreatic intraepithelial neoplasia lesions was also significantly suppressed. The Ki-67 labeling index was significantly lower in pancreatic carcinomas in the high-dose montelukast group than in controls. In vitro experiments revealed that montelukast suppressed proliferation of pancreatic cancer cells in a dose-dependent manner with decreased expression of phospho-ERK1/2. Montelukast induced G1 phase arrest. Conversely, leukotriene D (LTD), an agonist of CYSLTR1, increased cellular proliferation of pancreatic cancer cells with an accumulation of phospho-ERK1/2. In our cohort, pancreatic ductal adenocarcinoma patients with high CYSLTR1 expression showed a significantly unfavorable clinical outcome compared with those with low expression. Our results indicate that montelukast exerts a chemopreventive effect on pancreatic cancer via the LTD-CYSLTR1 axis and has potential for treatment of pancreatic carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22147444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304964PMC
July 2021

Suppressive Effect and Molecular Mechanism of Thunb. Extract against Prostate Carcinogenesis and Castration-Resistant Prostate Cancer.

Cancers (Basel) 2021 Jul 7;13(14). Epub 2021 Jul 7.

Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.

Thunb. (HCT) is a well-known Asian medicinal plant with biological activities used in the treatment of many diseases including cancer. This study investigated the effects of HCT extract and its ethyl acetate fraction (EA) on prostate carcinogenesis and castration-resistant prostate cancer (CRPC). HCT and EA induced apoptosis in androgen-sensitive prostate cancer cells (LNCaP) and CRPC cells (PCai1) through activation of caspases, down-regulation of androgen receptor, and inactivation of AKT/ERK/MAPK signaling. Rutin was found to be a major component in HCT (44.00 ± 5.61 mg/g) and EA (81.34 ± 5.21 mg/g) in a previous study. Rutin had similar effects to HCT/EA on LNCaP cells and was considered to be one of the active compounds. Moreover, HCT/EA inhibited cell migration and epithelial-mesenchymal transition phenotypes via STAT3/Snail/Twist pathways in LNCaP cells. The consumption of 1% HCT-mixed diet significantly decreased the incidence of adenocarcinoma in the lateral prostate lobe of the Transgenic rat for adenocarcinoma of prostate model. Similarly, tumor growth of PCai1 xenografts was significantly suppressed by 1% HCT treatment. HCT also induced caspase-dependent apoptosis via AKT inactivation in both in vivo models. Together, the results of in vitro and in vivo studies indicate that HCT has inhibitory effects against prostate carcinogenesis and CRPC. This plant therefore should receive more attention as a source for the future development of non-toxic chemopreventive agents against various cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13143403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306559PMC
July 2021

Intergenerational effect of short-term spaceflight in mice.

iScience 2021 Jul 25;24(7):102773. Epub 2021 Jun 25.

RIKEN Cluster for Pioneering Research, Tsukuba, Ibaraki 305-0074, Japan.

As space travel becomes more accessible, it is important to understand the effects of spaceflight including microgravity, cosmic radiation, and psychological stress. However, the effect on offspring has not been well studied in mammals. Here we investigated the effect of 35 days spaceflight on male germ cells. Male mice that had experienced spaceflight exhibit alterations in binding of transcription factor ATF7, a regulator of heterochromatin formation, on promoter regions in testis, as well as altered small RNA expression in spermatozoa. Offspring of space-traveling males exhibit elevated hepatic expression of genes related to DNA replication. These results indicate that spaceflight has intergenerational effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271179PMC
July 2021

Mathematical analysis of the effect of portal vein cells on biliary epithelial cell differentiation through the Delta-Notch signaling pathway.

BMC Res Notes 2021 Jun 29;14(1):243. Epub 2021 Jun 29.

Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Objective: The Delta-Notch signaling pathway induces fine-grained patterns of differentiation from initially homogeneous progenitor cells in many biological contexts, including Drosophila bristle formation, where mathematical modeling reportedly suggests the importance of production rate of the components of this signaling pathway. In contrast, the epithelial differentiation of bile ducts in the developing liver is unique in that it occurs around the portal vein cells, which express extremely high amounts of Delta ligands and act as a disturbance for the amount of Delta ligands in the field by affecting the expression levels of downstream target genes in the cells nearby. In the present study, we mathematically examined the dynamics of the Delta-Notch signaling pathway components in disturbance-driven biliary differentiation, using the model for fine-grained patterns of differentiation.

Results: A portal vein cell induced a high Notch signal in its neighboring cells, which corresponded to epithelial differentiation, depending on the production rates of Delta ligands and Notch receptors. In addition, this epithelial differentiation tended to occur in conditions where fine-grained patterning was reported to be lacking. These results highlighted the potential importance of the stability towards homogeneity determined by the production rates in Delta ligands and Notch receptors, in a disturbance-dependent epithelial differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13104-021-05656-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243745PMC
June 2021

Nuclear factor E2-related factor 2 (NRF2) deficiency accelerates fast fibre type transition in soleus muscle during space flight.

Commun Biol 2021 06 24;4(1):787. Epub 2021 Jun 24.

Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Microgravity induces skeletal muscle atrophy, particularly in the soleus muscle, which is predominantly composed of slow-twitch myofibre (type I) and is sensitive to disuse. Muscle atrophy is commonly known to be associated with increased production of reactive oxygen species. However, the role of NRF2, a master regulator of antioxidative response, in skeletal muscle plasticity during microgravity-induced atrophy, is not known. To investigate the role of NRF2 in skeletal muscle within a microgravity environment, wild-type and Nrf2-knockout (KO) mice were housed in the International Space Station for 31 days. Gene expression and histological analyses demonstrated that, under microgravity conditions, the transition of type I (oxidative) muscle fibres to type IIa (glycolytic) was accelerated in Nrf2-KO mice without affecting skeletal muscle mass. Therefore, our results suggest that NRF2 affects myofibre type transition during space flight.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-021-02334-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225765PMC
June 2021

Prognosis of patients with prostate cancer and bone metastasis from the Japanese Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index cohort study.

Int J Urol 2021 09 19;28(9):955-963. Epub 2021 Jun 19.

Department of Urology, Iwate Medical University, Yahaba, Japan.

Objective: To determine prognostic factors including the Bone Scan Index in prostate cancer patients receiving standard hormonal therapy and chemotherapy.

Methods: This multicenter Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index study involved 30 hospitals and enrolled 247 patients (age 71 ± 8 years) with metastatic hormone-sensitive prostate cancer (n = 148) under hormone therapy and metastatic castration-resistant prostate cancer (n = 99) under chemotherapy. The Bone Scan Index (%) was determined by whole-body bone scintigraphy using Tc-methylenediphosphonate. Patients were classified into tertiles and binary groups, and predictors of all-cause death including Bone Scan Index, prostate-specific antigen, and bone metabolic markers were determined using survival and proportional hazard analyses.

Results: During a mean follow-up period of 716 ± 404 days, 81 (33%) of the patients died, and 3-year mortality rates were 20% and 52% in the metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer groups, respectively. Survival analysis showed that a Bone Scan Index >3.5% was a significant determinant of death in the metastatic hormone-sensitive prostate cancer group, whereas prostate-specific antigen >55 ng/mL before chemotherapy was a determinant of prognosis in the metastatic castration-resistant prostate cancer group. A Bone Scan Index >3.5% was also associated with a high incidence of prostate-specific antigen progression in the metastatic hormone-sensitive prostate cancer group. Patients with metastatic hormone-sensitive prostate cancer and a better Bone Scan Index response (>45%) to treatment had lower mortality rates than those without such response.

Conclusion: The Bone Scan Index and hot spot number are significant determinants of 3-year mortality, and combining the Bone Scan Index with prostate-specific antigen should contribute to the management of prostate cancer patients with bone metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/iju.14614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453930PMC
September 2021

Cardiovascular safety of vibegron, a new β3-adrenoceptor agonist, in older patients with overactive bladder: Post-hoc analysis of a randomized, placebo-controlled, double-blind comparative phase 3 study.

Neurourol Urodyn 2021 08 17;40(6):1651-1660. Epub 2021 Jun 17.

Medical Affairs, Kyorin Pharmaceutical Co., Ltd., Toyko, Japan.

Aims: To examine the safety and efficacy of vibegron, a new β3-adrenoceptor agonist, in patients aged ≥65 years, with a focus on the effects on cardiovascular system and overactive bladder (OAB) symptoms.

Methods: A post-hoc subgroup analysis was performed of a randomized, placebo-controlled, double-blind comparative phase 3 study of vibegron, including those assigned to receive either vibegron 50 mg (V50), vibegron 100 mg (V100), or placebo for 12 weeks. Subjects were stratified into two subgroups based on age: a <65-year subgroup and a ≥65-year subgroup. Safety (changes in systolic and diastolic blood pressure, pulse rate, and residual urine volume) and efficacy (changes in the numbers of micturitions, urgency episodes, urgency urinary incontinence [UUI] episodes, and the voided volume/micturition) were assessed in the subgroups treated with vibegron vs. placebo.

Results: There were no significant differences in the cardiovascular outcomes (blood pressure and pulse rate), nor in the changes in residual urine volume, between the V50/100 and placebo groups in the <65-year or ≥65-year subgroup after 12-week treatment. Adverse events were slightly increased in the ≥65-year subgroup. In the efficacy analysis, V50/100 demonstrated similar efficacy in the <65-year and ≥65-year subgroups; an increasing trend in the voided volume/micturition was observed in subjects aged ≥65 years compared to subjects aged <65 years.

Conclusions: Vibegron was suggested to be similarly effective in patients ≥65 and <65 years and to have minimal influence on cardiovascular parameters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nau.24732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362047PMC
August 2021

Overexpression of human BAG3 in mice causes restrictive cardiomyopathy.

Nat Commun 2021 06 11;12(1):3575. Epub 2021 Jun 11.

Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Bonn, Germany.

An amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3-eGFP mice. The mutation renders hBAG3 less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3 and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23858-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196106PMC
June 2021

Generation and Characterization of a Cell Type-Specific, Inducible Cre-Driver Line to Study Olfactory Processing.

J Neurosci 2021 Jul 7;41(30):6449-6467. Epub 2021 Jun 7.

Sensory and Behavioural Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan, 904-0495

In sensory systems of the brain, mechanisms exist to extract distinct features from stimuli to generate a variety of behavioral repertoires. These often correspond to different cell types at various stages in sensory processing. In the mammalian olfactory system, complex information processing starts in the olfactory bulb, whose output is conveyed by mitral cells (MCs) and tufted cells (TCs). Despite many differences between them, and despite the crucial position they occupy in the information hierarchy, Cre-driver lines that distinguish them do not yet exist. Here, we sought to identify genes that are differentially expressed between MCs and TCs of the mouse, with an ultimate goal to generate a cell type-specific Cre-driver line, starting from a transcriptome analysis using a large and publicly available single-cell RNA-seq dataset (Zeisel et al., 2018). Many genes were differentially expressed, but only a few showed consistent expressions in MCs and at the specificity required. After further validating these putative markers using ISH, two genes (i.e., and ) remained as promising candidates. Using CRISPR/Cas9-mediated gene editing, we generated Cre-driver lines and analyzed the resulting recombination patterns. This indicated that our new inducible Cre-driver line, , can be used to genetically label MCs in a tamoxifen dose-dependent manner, both in male and female mice, as assessed by soma locations, projection patterns, and sensory-evoked responses Hence, this is a promising tool for investigating cell type-specific contributions to olfactory processing and demonstrates the power of publicly accessible data in accelerating science. In the brain, distinct cell types play unique roles. It is therefore important to have tools for studying unique cell types specifically. For the sense of smell in mammals, information is processed first by circuits of the olfactory bulb, where two types of cells, mitral cells and tufted cells, output different information. We generated a transgenic mouse line that enables mitral cells to be specifically labeled or manipulated. This was achieved by looking for genes that are specific to mitral cells using a large and public gene expression dataset, and creating a transgenic mouse using the gene editing technique, CRISPR/Cas9. This will allow scientists to better investigate parallel information processing underlying the sense of smell.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.3076-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318078PMC
July 2021

COMMD5 Inhibits Malignant Behavior of Renal Cancer Cells.

Anticancer Res 2021 Jun;41(6):2805-2815

Centre de Recherche, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.

Background/aim: Copper metabolism MURR1 domain-containing 5 (COMMD5) is mainly expressed in renal tubules (RTs), where it facilitates re-differentiation of injured RTs. We reported that COMMD5 regulates the expression of epidermal growth factor receptor by participating in its endocytic membrane trafficking, thus inhibiting tumor growth. Here we aimed to determine the role of COMMD5 in malignant phenotypes of renal cell carcinoma (RCC).

Materials And Methods: The associations between COMMD5 levels in RTs adjacent to RCC tumors in patients and their clinicopathologic characteristics were evaluated, and the effects of COMMD5 on cancer stemness in RCC cells were investigated.

Results: Low COMMD5 levels in RTs correlated with high tumorigenesis and poor patient outcomes. COMMD5 overexpression in RCC cells reduced the proportion of cancer stem cell-like cells and their malignant phenotypes, including proliferation, invasion and sphere formation. Secreted COMMD5 from RT cells also reduced malignant phenotypes.

Conclusion: COMMD5 might suppress malignant phenotypes of RCC, thus inhibiting tumor development and improving patient prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.15061DOI Listing
June 2021

Starvation-induced transcription factor CREBH negatively governs body growth by controlling GH signaling.

FASEB J 2021 06;35(6):e21663

Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

cAMP responsive element-binding protein H (CREBH) is a hepatic transcription factor to be activated during fasting. We generated CREBH knock-in flox mice, and then generated liver-specific CREBH transgenic (CREBH L-Tg) mice in an active form. CREBH L-Tg mice showed a delay in growth in the postnatal stage. Plasma growth hormone (GH) levels were significantly increased in CREBH L-Tg mice, but plasma insulin-like growth factor 1 (IGF1) levels were significantly decreased, indicating GH resistance. In addition, CREBH overexpression significantly increased hepatic mRNA and plasma levels of FGF21, which is thought to be as one of the causes of growth delay. However, the additional ablation of FGF21 in CREBH L-Tg mice could not correct GH resistance at all. CREBH L-Tg mice sustained GH receptor (GHR) reduction and the increase of IGF binding protein 1 (IGFBP1) in the liver regardless of FGF21. As GHR is a first step in GH signaling, the reduction of GHR leads to impairment of GH signaling. These data suggest that CREBH negatively regulates growth in the postnatal growth stage via various pathways as an abundant energy response by antagonizing GH signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.202002784RRDOI Listing
June 2021

Findings from recent studies by the Japan Aerospace Exploration Agency examining musculoskeletal atrophy in space and on Earth.

NPJ Microgravity 2021 May 26;7(1):18. Epub 2021 May 26.

Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

The musculoskeletal system provides the body with correct posture, support, stability, and mobility. It is composed of the bones, muscles, cartilage, tendons, ligaments, joints, and other connective tissues. Without effective countermeasures, prolonged spaceflight under microgravity results in marked muscle and bone atrophy. The molecular and physiological mechanisms of this atrophy under unloaded conditions are gradually being revealed through spaceflight experiments conducted by the Japan Aerospace Exploration Agency using a variety of model organisms, including both aquatic and terrestrial animals, and terrestrial experiments conducted under the Living in Space project of the Japan Ministry of Education, Culture, Sports, Science, and Technology. Increasing our knowledge in this field will lead not only to an understanding of how to prevent muscle and bone atrophy in humans undergoing long-term space voyages but also to an understanding of countermeasures against age-related locomotive syndrome in the elderly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41526-021-00145-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155041PMC
May 2021

Identification of microRNA-96-5p as a postoperative, prognostic microRNA predictor in nonviral hepatocellular carcinoma.

Hepatol Res 2021 May 26. Epub 2021 May 26.

Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Aim: The microRNA (miR) clusters miR-183/96/182 and miR-217/216a/216b are significantly upregulated in nonviral hepatocellular carcinoma (NBNC-HCC). Here, we investigate the impact of each member of these clusters on the clinical outcome of NBNC-HCC and analyze the antitumor effects of miR-96-5p.

Methods: The association between recurrence-free survival of 111 NBNC-HCC patients and the levels of miR-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, miR-216a-5p, and miR-216b-5p in tumor and adjacent tissues was investigated. The impact of miR-96-5p on apoptosis and invasion of a hepatoma cell line, HepG2, was investigated by cell counting, Transwell assay, and flow cytometry, respectively.

Results: MicroRNA-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, and miR-216b-5p were significantly upregulated in tumor tissues compared to the adjacent tissues (p = 0.0005, p = 0.0030, p = 0.0002, p = 0.0011, and p = 0.0288, respectively). By multivariate Cox regression analysis, high tumor/adjacent ratios of miR-182-5p (p = 0.007) and miR-217-5p (p = 0.008) were associated with poor recurrence-free survival. In contrast, a low tumor/adjacent ratio of miR-96-5p (p < 0.001) was associated with poor recurrence-free survival. It suggested that further upregulation of miR-96-5p in tumors might have an inhibitory effect on recurrence. Transfection of miR-96-5p mimic significantly induced apoptosis of HepG2 cells, in association with downregulation of Nucleophosmin 1 (NPM1) and a decrease of phosphorylated AKT protein. Interestingly, simultaneous knockdown of the NPM1 and AKT genes induced apoptosis. MicroRNA-96-5p also suppressed proliferation and invasion, which inhibited epithelial-to-mesenchymal transition of HCC cells.

Conclusion: MicroRNA-96-5p as a tumor suppressor would be valuable to stratify NBNC-HCC patients at high risk of recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hepr.13674DOI Listing
May 2021

Osteosarcoma-Derived Small Extracellular Vesicles Enhance Tumor Metastasis and Suppress Osteoclastogenesis by miR-146a-5p.

Front Oncol 2021 4;11:667109. Epub 2021 May 4.

Department of Immunology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

Osteosarcoma is the most frequent type of primary bone tumor in children and adolescents, thus care for patients with malignant osteosarcoma is strongly required. The roles of small extracellular vesicles (SEVs) in enhancing metastases have been demonstrated in multiple tumors, but they are still poorly understood in osteosarcoma. Hence, this study investigated the effects of SEVs on progression and the tumor microenvironment in mice and patients. In an orthotopic implantation study, we found that osteosarcoma-derived SEVs had the potential to enhance metastases and angiogenesis. In addition, osteosarcoma-derived SEVs decreased the number of mature osteoclasts . osteoclastogenesis studies revealed that the inhibition of osteoclast maturation by osteosarcoma-derived SEVs was mediated by suppressing the NF-κB signal pathway. MicroRNA analysis of SEVs from different malignant human osteosarcomas revealed that miR-146a-5p was involved in the inhibition of osteoclastogenesis. In osteosarcoma patients, lower numbers of osteoclasts in biopsy specimens at the first visits were correlated with higher malignancy. These findings indicated that osteosarcoma-derived SEVs enhance distant metastasis of osteosarcomas by inhibiting osteoclast maturation, which may be a useful prognostic marker. This diagnostic method may enable to predict malignancy at early stage, and help to provide optimal care to patients with risk of high malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.667109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130824PMC
May 2021

Radiation inducible MafB gene is required for thymic regeneration.

Sci Rep 2021 05 17;11(1):10439. Epub 2021 May 17.

Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama, 641-8509, Japan.

The thymus facilitates mature T cell production by providing a suitable stromal microenvironment. This microenvironment is impaired by radiation and aging which lead to immune system disturbances known as thymic involution. Young adult thymus shows thymic recovery after such involution. Although various genes have been reported for thymocytes and thymic epithelial cells in such processes, the roles of stromal transcription factors in these remain incompletely understood. MafB (v-maf musculoaponeurotic fibrosarcoma oncogene homolog B) is a transcription factor expressed in thymic stroma and its expression was induced a day after radiation exposure. Hence, the roles of mesenchymal MafB in the process of thymic regeneration offers an intriguing research topic also for radiation biology. The current study investigated whether MafB plays roles in the adult thymus. MafB/green fluorescent protein knock-in mutant (MafB) mice showed impaired thymic regeneration after the sublethal irradiation, judged by reduced thymus size, total thymocyte number and medullary complexity. Furthermore, IL4 was induced after irradiation and such induction was reduced in mutant mice. The mutants also displayed signs of accelerated age-related thymic involution. Altogether, these results suggest possible functions of MafB in the processes of thymic recovery after irradiation, and maintenance during aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-89836-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129107PMC
May 2021

EXOC1 plays an integral role in spermatogonia pseudopod elongation and spermatocyte stable syncytium formation in mice.

Elife 2021 05 11;10. Epub 2021 May 11.

Laboratory Animal Resource Center, Trans-border Medical Research Center, University of Tsukuba, Tsukuba, Japan.

The male germ cells must adopt the correct morphology at each differentiation stage for proper spermatogenesis. The spermatogonia regulates its differentiation state by its own migration. The male germ cells differentiate and mature with the formation of syncytia, failure of forming the appropriate syncytia results in the arrest at the spermatocyte stage. However, the detailed molecular mechanisms of male germ cell morphological regulation are unknown. Here, we found that EXOC1, a member of the Exocyst complex, is important for the pseudopod formation of spermatogonia and spermatocyte syncytia in mice. EXOC1 contributes to the pseudopod formation of spermatogonia by inactivating the Rho family small GTPase Rac1 and also functions in the spermatocyte syncytia with the SNARE proteins STX2 and SNAP23. Since EXOC1 is known to bind to several cell morphogenesis factors, this study is expected to be the starting point for the discovery of many morphological regulators of male germ cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.59759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112867PMC
May 2021

Disruption of entire locus leads to embryonic lethality by diminished gene expression and enhanced p53 pathway.

Elife 2021 05 5;10. Epub 2021 May 5.

Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

In vivo function of CDK5 and Abl enzyme substrate 2 (Cables2), belonging to the Cables protein family, is unknown. Here, we found that targeted disruption of the entire locus () caused growth retardation and enhanced apoptosis at the gastrulation stage and then induced embryonic lethality in mice. Comparative transcriptome analysis revealed disruption of , 50% down-regulation of abutting on the locus, and up-regulation of p53-target genes in gastrulas. We further revealed the lethality phenotype in -deleted mice and unexpectedly, the exon 1-deleted mice survived. Interestingly, chimeric mice derived from ESCs carrying exogenous and tetraploid wild-type embryo overcame gastrulation. These results suggest that the diminished expression of and the completed lack of expression are intricately involved in the embryonic lethality via the p53 pathway. This study sheds light on the importance of locus in mouse embryonic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.50346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099427PMC
May 2021

Stereotyped Upper Limb Movement in Duplication Syndrome.

Neurology 2021 07 30;97(2):92-94. Epub 2021 Apr 30.

From the Department of Pediatrics (T.W., S.F., K.T., S.K., T.T., Y.K.), Sapporo Medical University School of Medicine; Department of Pediatrics (S.T.), Asahikawa Medical University, Hokkaido; Division of Medical Genetics (K.K.), Kanagawa Children's Medical Center; and Departments of Gastroenterology (S.M.) and Pediatrics (T.W., Y.S.), Hakodate Municipal Hospital, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000012130DOI Listing
July 2021

Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment.

Sci Rep 2021 04 28;11(1):9168. Epub 2021 Apr 28.

Mouse Epigenetics Project, ISS/Kibo Experiment, Japan Aerospace Exploration Agency (JAXA), Ibaraki, 305-8505, Japan.

Spaceflight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artificial earth-gravity (artificial 1 g; AG) and microgravity (μg; MG), to investigate whether artificial 1 g exposure prevents muscle atrophy at the molecular level. Our main findings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fiber type composition but also in the alteration of gene expression profiles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy-related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profiles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-88392-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080648PMC
April 2021

The validity of the claims-based definition of rheumatoid arthritis evaluated in 64 hospitals in Japan.

BMC Musculoskelet Disord 2021 Apr 22;22(1):373. Epub 2021 Apr 22.

Rheumatology Center, Chiba-Nishi General Hospital, Matsudo, Chiba, Japan.

Background: An administrative database covering a whole population such as the national database in Japan may be used to estimate the nationwide prevalence of diseases including rheumatoid arthritis (RA) when a well-validated definition of the disease is available. In Japan, the record linkage between the administrative database and medical charts in hospitals is strictly prohibited. A "hospital-based" validation study is one of few possible validation studies where claims kept inside the study hospital are rearranged into the database structure.

Methods: We selected random samples of 19,734 patients from approximately 1.6 million patients who received medical care between February 2018 and January 2019 in one of the 64 hospitals of the Tokushukai Medical Group. We excluded patients whose observation period was less than 365 days and identified 334 patients who met the definition of "possible cases of RA" whose medical charts were then independently evaluated by two rheumatologists. In a sensitivity analysis, we assessed bias due to misclassifying some patients with RA who did not meet the definition of "possible cases of RA" as a patient with no RA.

Results: The kappa coefficient between the two rheumatologists was 0.80. The prevalence of RA in the study population was estimated to be 0.56%. We found that [condition code of RA] and ([any disease-modifying antirheumatic drug] or [oral corticosteroid with no systemic autoimmune diseases (other than RA) and no polymyalgia rheumatica]) had a relatively high sensitivity (approximately 73%) and a high positive predictive value (approximately 80%). In a sensitivity analysis, we found that when some patients with RA who did not meet the definition of "possible cases of RA" were misclassified as a patient with no RA, then this would lead to underestimation of the prevalence of the definition-positive patients and the adjusted prevalence.

Conclusions: We recommend using the claims-based definition of RA (found in the current validation study) to estimate the prevalence of RA in Japan. We also suggest estimating the adjusted prevalence using the quantitative bias analysis method, since the prevalence of the disease in the "hospital-based" validation study is different from that in the administrative database.

Trial Registration: The current study is not a clinical trial and hence not subject to trial registration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12891-021-04259-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063301PMC
April 2021
-->