Publications by authors named "Masami Watanabe"

265 Publications

ABO Blood Incompatibility Positively Affects Early Graft Function: Single-Center Retrospective Cohort Study.

Transplant Proc 2021 Apr 27. Epub 2021 Apr 27.

Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Kita-ku, Okayama, Japan.

Background: We investigated the association between ABO-incompatible (ABO-I) kidney transplantation and early graft function.

Methods: We retrospectively analyzed 95 patients who underwent living donor kidney transplantation between May 2009 and July 2019. It included 61 ABO-compatible (ABO-C) and 34 ABO-I transplantations. We extracted data on immunologic profile, sex, age, cold ischemic time, type of immunosuppression, and graft function. Two definitions were used for slow graft function (SGF) as follows: postoperative day (POD) 3 serum creatinine level >3 mg/dL and estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m. Logistic regression analysis was performed to analyze the effect of ABO-I on the incidence of SGF.

Results: The characteristics between the ABO-C and ABO-I were not different. ABO-I received rituximab and plasma exchange. Patients also received tacrolimus and mycophenolate mofetil for 2 weeks and prednisolone for 1 week before transplantation as preconditioning. Of the 95 study patients, 19 (20%) and 21 (22%) were identified with SGF according to POD 3 serum creatinine level or eGFR, respectively. Multivariable analysis revealed that ABO-I significantly reduced the incidence of SGF (odds ratio, 0.15; 95% confidence interval, 0.03-0.7; P = .02), and cold ischemic time >150 min increased the incidence of SGF (odds ratio, 6.5; 95% confidence interval, 1.7-25; P = .006). Similar results were identified in POD 3 eGFR. Inferior graft function in patients with SGF was identified up to 6 months after transplantation.

Conclusion: ABO-I reduces the incidence of SGF, which is associated with an inferior graft function up to 6 months.
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http://dx.doi.org/10.1016/j.transproceed.2021.03.043DOI Listing
April 2021

Evaluation of Neutrophil Dynamics Change by Protective Effect of Tadalafil After Renal Ischemia/Reperfusion Using In Vivo Real-time Imaging.

Transplantation 2021 Apr 27. Epub 2021 Apr 27.

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan.

Background: Neutrophils play a major role in ischemia/reperfusion injury (IRI) in renal transplantation and acute kidney injury. However, it has been difficult to observe changes in neutrophil dynamics over time in living mice kidney. We investigate neutrophil dynamics in IRI in living mice using novel in vivo multiphoton microscope imaging techniques and characterize the renoprotective effects of a selective phosphodiesterase (PDE) 5 inhibitor, tadalafil.

Methods: Wild-type (WT) and eNOS knockout (eNOS-KO) mice, a model of endothelial dysfunction, were used to establish in vivo real-time imaging in living mouse kidneys. Neutrophils were labeled green with Ly-6G monoclonal antibody, and plasma flow was labeled red with bovine serum albumin. Tadalafil was administered orally 1 h before surgery. Both kidney pedicles were reperfused after 37° warm ischemia for 45 min.

Results: Our novel approach revealed that neutrophils were trapped in glomerulus within a few minutes after reperfusion. They gradually increased over time and Infiltrated neutrophils were observed in the tubular lumen and peritubular capillary. The neutrophils were clearly visualized rolling on peritubular capillary plexus at 3 μm/min. The administration of tadalafil significantly reduced neutrophil influx into the glomerulus in both WT and eNOS-KO mice. Reduced neutrophil infiltration in tadalafil groups, which was confirmed by flow cytometry, resulted in histopathologically decreased tubular injury. The expression of VCAM-1 and KIM-1 was partially prevented by tadalafil.

Conclusions: Use of a novel technique contributed to elucidation of neutrophil dynamics after reperfusion. Tadalafil has a potential for inhibiting neutrophil infiltration in renal IRI.Supplemental Visual Abstract; http://links.lww.com/TP/C223.
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http://dx.doi.org/10.1097/TP.0000000000003803DOI Listing
April 2021

Successful deceased donor kidney transplantation to a recipient with a history of COVID-19 treatment.

J Infect Chemother 2021 Mar 29. Epub 2021 Mar 29.

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Case Presentation: A 49-year-old Asian male, who had undergone hemodialysis for >16 years, complained of a fever, dysgeusia and dysosmia, and was diagnosed with COVID-19 pneumonia based on severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (SARS-CoV-2 PCR) and computed tomography (CT). Treatment was started with oral favipiravir and ciclesonide inhalation. On the 10th day of treatment, the patient had a persistent high fever and a chest CT showed exacerbation of pneumonia, so dexamethasone was intravenously started. He was discharged after confirming two consecutive negative SARS-CoV-2 PCR tests. Three months after COVID-19 treatment, a SARS-CoV-2 PCR test was negative and he underwent a deceased donor kidney transplantation. Basiliximab induction with triple drug immunosuppression consisting of extended-release tacrolimus, mycophenolate mofetil and prednisolone, which is our regular immunosuppression protocol, was used. He was discharged on postoperative day 18 without the need for postoperative hemodialysis or any complications. The serum creatinine level was 1.72 mg/dL 95 days postoperatively and he had a favorable clinical course that was similar to deceased donor kidney recipients without a history of SARS-CoV-2 infection.

Conclusion: We report the first case of a kidney transplantation after COVID-19 treatment in Japan and the fourth case globally. We would like to provide information about our successful case due to the anticipated increase in similar candidates in the near future.
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http://dx.doi.org/10.1016/j.jiac.2021.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006195PMC
March 2021

Dual-Functional PLGA Nanoparticles Co-Loaded with Indocyanine Green and Resiquimod for Prostate Cancer Treatment.

Int J Nanomedicine 2021 12;16:2775-2787. Epub 2021 Apr 12.

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

Purpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men's health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment.

Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation.

Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9±1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96±1.88)% compared with (0.99±0.10)% in PBS group, revealing the enhanced immune response against PCa.

Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy.
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http://dx.doi.org/10.2147/IJN.S301552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052122PMC
May 2021

Pancreas preservation with amphotericin B deteriorates islet yield for porcine islet isolation.

Xenotransplantation 2021 Apr 2:e12690. Epub 2021 Apr 2.

Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

Background: Amphotericin B is a crucial agent in the management of serious systemic fungal infections. It is also known to be cytotoxic. In this study, we evaluated the effect of amphotericin B added to the preservation solution on islet yield during islet isolation.

Methods: Porcine pancreata were preserved in the preservation solution with or without amphotericin B (0.25 μg/mL) for approximately 18 hours at 4°C, and then islet isolation was performed. An optimized number (1750 IE) of isolated islets from each group were transplanted into streptozotocin-induced diabetic mice. The culture of isolated islets and acinar tissue with amphotericin B was also evaluated.

Results: The islet yield before and after purification in the amphotericin B (-) group was significantly higher than that in the amphotericin B (+) group. After islet transplantation into diabetic mice, blood glucose levels reached the normoglycemic range, with 50% and 0% of that of the diabetic mice in the amphotericin B (-) and amphotericin B (+) groups, respectively. In the culture study, amphotericin B was found to be cytotoxic to porcine islets and acinar tissue.

Conclusions: Amphotericin B added to the preservation solution deteriorates islet yield during porcine islet isolation. Thus, the use of amphotericin B should be considered carefully for the preservation of the pancreas for islet isolation and islet culture before islet transplantation.
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http://dx.doi.org/10.1111/xen.12690DOI Listing
April 2021

Impact of paclitaxel, cisplatin, and gemcitabine as first-line chemotherapy in cisplatin-fit and -unfit patients with advanced/metastatic urothelial carcinoma.

Urol Oncol 2021 Mar 25. Epub 2021 Mar 25.

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

Purpose: This study aimed to clarify the efficacy and toxicity of first-line combination treatment with paclitaxel, cisplatin, and gemcitabine (PCG) for advanced/metastatic urothelial carcinoma (UC) in cisplatin-unfit patients compared with cisplatin-fit patients.

Methods: We conducted a retrospective study of patients who received first-line PCG. Using international consensus criteria, patients were classified into cisplatin-fit and -unfit groups. Cisplatin-unfit patients received PCG with adjustment of the cisplatin dose after assessing 24-hour urinary creatinine clearance, without modifying the administration interval.

Results: From 2008 to 2017, 50 patients received first-line PCG, of whom 30 and 20 were classified into the cisplatin-fit and -unfit groups. After a median follow-up of 15.0 months, the median overall survival (OS) and progression-free survival (PFS) were 15.0 and 9.8 months in all patients, 15.0 and 10.0 months in the cisplatin-fit group, and 13.2 and 9.3 months in the cisplatin-unfit group, respectively. There was no significant difference in OS (hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 0.69-2.54) or PFS (HR: 1.38, 95% CI: 0.74-2.55) between the groups. The overall response rate and complete response rate were 58% (95% CI: 43.2-71.8) and 32% (95% CI: 19.5-46.7) in all patients, and 55% (95% CI: 31.5-76.9) and 35% (95% CI: 15.4-59.2) in the cisplatin-unfit group, respectively. The common grade 3 of 4 adverse events experienced were neutropenia (78%), followed by thrombocytopenia (56%), anemia (46%), and febrile neutropenia (16%). The 24-hour urinary creatinine clearance did not differ significantly between the groups after one, two, or three courses of PCG.

Conclusions: We found no significant difference regarding OS and PFS between the cisplatin-fit patients with a full dose of cisplatin and -unfit patients with cisplatin-dose-adjusted chemotherapy. In select cisplatin-unfit patients, PCG with dose adjustment of cisplatin may be useful for treating advanced/metastatic UC without any significant adverse events or impaired renal function compared with cisplatin-fit patients with a full dose of cisplatin.
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http://dx.doi.org/10.1016/j.urolonc.2021.02.029DOI Listing
March 2021

Photodynamic diagnostic ureteroscopy using the VISERA ELITE video system for diagnosis of upper-urinary tract urothelial carcinoma: a prospective cohort pilot study.

BMC Urol 2021 Mar 25;21(1):45. Epub 2021 Mar 25.

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Background: The advantages of photodynamic diagnostic technology using 5-aminolevulinic acid (ALA-PDD) have been established. The aim of this prospective cohort study was to evaluate the usefulness of ALA-PDD to diagnose upper tract urothelial carcinoma (UT-UC) using the Olympus VISERA ELITE video system.

Methods: We carried out a prospective, interventional, non-randomized, non-contrast and open label cohort pilot study that involved patients who underwent ureterorenoscopy (URS) to detect UT-UC. 5-aminolevulinic acid hydrochloride was orally administered before URS. The observational results and pathological diagnosis with ALA-PDD and traditional white light methods were compared, and the proportion of positive subjects and specimens were calculated.

Results: A total of 20 patients were enrolled and one patient who had multiple bladder tumors did not undergo URS. Fifteen of 19 patients were pathologically diagnosed with UT-UC and of these 11 (73.3%) were ALA-PDD positive. Fourteen of 19 patients were ALA-PDD positive and of these 11 were pathologically diagnosed with UC. For the 92 biopsy specimens that were malignant or benign, the sensitivity for both traditional white light observation and ALA-PDD was the same at 62.5%, whereas the specificities were 73.1% and 67.3%, respectively. Of the 38 specimens that were randomly biopsied without any abnormality under examination by both white light and ALA-PDD, 11 specimens (28.9%) from 5 patients were diagnosed with high grade UC. In contrast, four specimens from 4 patients, which were negative in traditional white light observation but positive in ALA-PDD, were diagnosed with carcinoma in situ (CIS).

Conclusions: Our results suggest that ALA-PDD using VISERA ELITE is not sufficiently applicable for UT-UC. Nevertheless, it might be better particularly for CIS than white light and superior results would be obtained using VISERA ELITE II video system.

Trial Registration: The present clinical study was approved by the Okayama University Institutional Review Board prior to study initiation (Application no.: RIN 1803-002) and was registered with the UMIN Clinical Trials Registry (UMIN-CTR), Japan (Accession no.: UMIN000031205).
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http://dx.doi.org/10.1186/s12894-021-00819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995577PMC
March 2021

The role of Wnt signaling in male reproductive physiology and pathology.

Mol Hum Reprod 2021 01;27(1)

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

Accumulating evidence has shown that Wnt signaling is deeply involved in male reproductive physiology, and malfunction of the signal path can cause pathological changes in genital organs and sperm cells. These abnormalities are diverse in manifestation and have been constantly found in the knockout models of Wnt studies. Nevertheless, most of the research solely focused on a certain factor in the Wnt pathway, and there are few reports on the overall relation between Wnt signals and male reproductive physiology. In our review, Wnt findings relating to the reproductive system were sought and summarized in terms of Wnt ligands, Wnt receptors, Wnt intracellular signals and Wnt regulators. By sorting out and integrating relevant functions, as well as underlining the controversies among different reports, our review aims to offer an overview of Wnt signaling in male reproductive physiology and pathology for further mechanistic studies.
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http://dx.doi.org/10.1093/molehr/gaaa085DOI Listing
January 2021

Gene Expression in Pancreatic Cancer-Like Cells and Induced Pancreatic Stem Cells Generated by Transient Overexpression of Reprogramming Factors.

J Clin Med 2021 Jan 25;10(3). Epub 2021 Jan 25.

Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.

We previously reported that transient overexpression of reprogramming factors can be used to generate induced pluripotent stem (iPS) cells, induced tissue-specific stem (iTS) cells, and fibroblast-like (iF) cells from pancreatic tissue. iF cells have tumorigenic ability and behave similarly to pancreatic cancer cells. In this study, we analyzed gene expression in iF cells and iTS-P cells (iTS cells from pancreatic tissue) via microarray analysis and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression levels of the Mybl2 and Lyn genes, which are reported to be oncogenes, were significantly higher in iF cells than in iTS-P cells. The expression level of Nestin, which is expressed in not only pancreatic progenitor cells but also pancreatic ductal adenocarcinomas, was also higher in iF cells than in iTS-P cells. Itgb6 and Fgf13, which are involved in the pathogenesis of diseases such as cancer, exhibited higher expression levels in iF cells than in iTS-P cells. Unexpectedly, the expression levels of genes related to epithelial-mesenchymal transition (EMT), except Bmp4, were lower in iF cells than in iTS-P cells. These data suggest that the Mybl2, Lyn, Nestin, Itgb6, and Fgf13 genes could be important biomarkers to distinguish iTS-P cells from iF cells.
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http://dx.doi.org/10.3390/jcm10030454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865593PMC
January 2021

Impact of Sarcopenia on Erectile Function after Nerve-Sparing Robot-Assisted Radical Prostatectomy.

World J Mens Health 2020 Nov 16. Epub 2020 Nov 16.

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

Purpose: To determine the impact of sarcopenia on erectile functional outcomes after a nerve-sparing (NS) robot-assisted radical prostatectomy (RARP) using patient-reported validated questionnaires.

Materials And Methods: In this retrospective study, RARP was performed on 841 patients at Okayama University Hospital, of which 132 underwent NS RARP. Erectile functional outcomes were assessed using the 5-item version of the International Index of Erectile Function (IIEF-5) and the Expanded Prostate Cancer Index Composite before and 1, 3, 6, and 12 months after surgery. Automated measurement of skeletal muscle at L3 was achieved using volume analyzer software and normalizing for height (cm²/m²) to calculate skeletal muscle index (SMI). Patients who had an IIEF-5≤4 comprised the group with erectile dysfunction (ED), and those with an IIEF-5≤5 made up the non-ED group.

Results: This study enrolled 95 patients of median age 65 years with a preoperative IIEF-5 of 16. There were no significant differences between patients with and without sarcopenia among those with preoperative IIEF-5. Postoperatively, in the ED group, SMI and preoperative IIEF-5 were significantly lower than in the non-ED group. Multiple linear regression analysis revealed that (1) both SMI and preoperative IIEF-5 were independent predictors of ED, and (2) sarcopenia and preoperative IIEF-5 were predictors of ED at 12 months after NS RARP.

Conclusions: Patients with sarcopenia can have worse erectile functional outcomes after NS RARP. Sarcopenia and a lower preoperative IIEF-5 score may be predictive of postoperative ED.
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http://dx.doi.org/10.5534/wjmh.200036DOI Listing
November 2020

Pancreas preservation in extracellular-type p38 inhibitor-containing solution improves islet yield for porcine islet isolation.

Xenotransplantation 2021 Mar 24;28(2):e12661. Epub 2020 Nov 24.

Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Background: For islet transplantation, pancreas preservation and islet isolation activate p38, which is a member of the stress-activated group of mitogen-activated protein kinases (MAPKs). In this study, we evaluated an extracellular-type p38 inhibitor-containing (EP) solution with University of Wisconsin (UW) solution, the gold standard for organ preservation. The EP solution has high sodium-low potassium composition with low viscosity compared to UW solution. Moreover, EP solution contains a recently developed p38 inhibitor (11R-p38I ) from our laboratory.

Methods: Porcine pancreata were preserved in UW, EP, or EP-P solution (EP solution without 11R-p38I ), and then islet isolation was performed. An optimized number (1500 IE) of isolated islets from each group were transplanted into streptozotocin-induced diabetic mice.

Results: The islet yield before and after purification was significantly higher in the EP group than in the UW group. The islet yield before and after purification was not significantly different between the EP and EP-P groups; however, the EP solution prevented a reduction in the number of islets during culture. Western blot analysis showed that p38 activation was attenuated by EP solution. For islet transplantation into streptozotocin-induced diabetic mice, pancreas preservation in EP solution improved the outcome of islet transplantation.

Conclusions: Pancreas preservation with EP solution preserved islet function better than with UW solution. The advantages of EP solution over UW solution may include the inhibition of p38 activity as well as the composition of the solution.
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http://dx.doi.org/10.1111/xen.12661DOI Listing
March 2021

Preservation of pancreas in the University of Wisconsin solution supplemented with AP39 reduces reactive oxygen species production and improves islet graft function.

Am J Transplant 2020 Nov 19. Epub 2020 Nov 19.

Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Ischemia-reperfusion injury (IRI) results in increased rates of delayed graft function and early graft loss. It has recently been reported that hydrogen sulfide (H S) protects organ grafts against prolonged IRI. Here, we investigated whether the preservation of pancreas in University of Wisconsin (UW) solution supplemented with AP39, which is a mitochondrial-targeted H S donor, protected pancreatic islets against IRI and improved islet function. Porcine pancreata were preserved in the UW solution with AP39 (UW + AP39) or the vehicle (UW) for 18 h, followed by islet isolation. The islet yields before and after purification were significantly higher in the UW + AP39 group than in the UW group. The islets isolated from the pancreas preserved in UW + AP39 exhibited significantly decreased levels of reactive oxygen species (ROS) production and a significantly increased mitochondrial membrane potential as compared to the islets isolated from the pancreas preserved in the vehicle. We found that the pancreas preserved in UW + AP39 improved the outcome of islet transplantation in streptozotocin-induced diabetic mice. These results suggest that the preservation of pancreas in UW + AP39 protects the islet grafts against IRI and could thus serve as a novel clinical strategy for improving islet transplantation outcomes.
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http://dx.doi.org/10.1111/ajt.16401DOI Listing
November 2020

Evidence for a role of nitric oxide in iron homeostasis in plants.

J Exp Bot 2021 Feb;72(4):990-1006

Laboratory of Plant Biochemistry, Chiba University, Inage-ward, Yayoicho, Chiba, Japan.

Nitric oxide (NO), once regarded as a poisonous air pollutant, is now understood as a regulatory molecule essential for several biological functions in plants. In this review, we summarize NO generation in different plant organs and cellular compartments, and also discuss the role of NO in iron (Fe) homeostasis, particularly in Fe-deficient plants. Fe is one of the most limiting essential nutrient elements for plants. Plants often exhibit Fe deficiency symptoms despite sufficient tissue Fe concentrations. NO appears to not only up-regulate Fe uptake mechanisms but also makes Fe more bioavailable for metabolic functions. NO forms complexes with Fe, which can then be delivered into target cells/tissues. NO generated in plants can alleviate oxidative stress by regulating antioxidant defense processes, probably by improving functional Fe status and by inducing post-translational modifications in the enzymes/proteins involved in antioxidant defense responses. It is hypothesized that NO acts in cooperation with transcription factors such as bHLHs, FIT, and IRO to regulate the expression of enzymes and proteins essential for Fe homeostasis. However, further investigations are needed to disentangle the interaction of NO with intracellular target molecules that leads to enhanced internal Fe availability in plants.
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http://dx.doi.org/10.1093/jxb/eraa484DOI Listing
February 2021

The number of glutamines in the N-terminal of the canine androgen receptor affects signalling intensities.

Vet Comp Oncol 2021 Jun 16;19(2):399-403. Epub 2020 Nov 16.

School of Veterinary Nursing and Technology, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo, Japan.

Most male dogs are castrated at young ages, making them easy to rear following androgen deprivation. Although the incidence of canine prostate cancer is low, several patients have resistance to androgen therapy and poor clinical prognosis. These outcomes are similar to those of end-stage human androgen-independent prostate cancer. The androgen receptor (AR) of canines has two polyglutamine (polyQ) sequences (Q × 10 and Q × 23) at its N-terminal. The length of polyQ may be a risk factor for the development of prostate cancer in dogs; however, there is no evidence to support this. Hence, we artificially created polyQ deletion mutants of canine AR and evaluated their effects on AR signalling. The deletions of Q × 10 and Q × 23 were associated with significant reductions in AR signalling intensities. The Q × 10 mutants, which increase or decrease Q sequentially, also altered AR signalling. Furthermore, the Q × 10 deletion mutant, compared with the Q × 10 control, altered the intensities of the binding of polyQ to the C-terminal of AR, which contains a ligand-binding domain; this was not observed with the Q × 9, 11, and 12 variants. The number of glutamines in the N-terminals of canine ARs may influence AR signalling intensities and contribute to the risk of prostate cancer in dogs.
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http://dx.doi.org/10.1111/vco.12663DOI Listing
June 2021

Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability.

Oncol Lett 2020 Dec 11;20(6):351. Epub 2020 Oct 11.

School of Veterinary Nursing and Technology, Faculty of Veterinary Science, Musashino, Tokyo 180-8602, Japan.

Isocitrate dehydrogenase 1 (IDH1) mutations are common in gliomas, acute myeloid leukemia, and chondrosarcoma. The mutation 'hotspot' is a single arginine residue, R132. The R132H mutant of IDH1 produces the 2-hydroxyglutarate (2-HG) carcinogen from α-ketoglutarate (α-KG). The reduction of α-KG induces the accumulation of hypoxia-inducible factor-1α subunit (HIF-1α) in the cytosol, which is a predisposing factor for carcinogenesis. R132H is the most common IDH1 mutation in humans, but mutations at the R132 residue can also occur in tumor tissues of dogs. The current study reported the discovery of a novel Tyr208Cys (Y208C) mutation in canine IDH1 (cIDH1), which was isolated from 2 of 45 canine chondrosarcoma cases. As the genomic DNA isolated from chondrosarcoma tissue was mutated, but that isolated from blood was not, Y208C mutations were considered to be spontaneous somatic mutations. The isocitrate dehydrogenase activity of the Y208C mutant was attenuated compared with that of wild-type (WT) cIDH1, but the attenuation of Y208C was less intense than that of the R132H mutation. The induction of HIF-1α response element activity and cell retention of HIF-1α were not increased by Y208C overexpression. and cell biological analysis of IDH1 dimerization revealed that the Y208C mutation, but not the R132H mutation, attenuated binding activity with WT cIDH1. These data suggested that the attenuation of dimerization by the Y208C mutation may cause tumorigenesis through different mechanisms other than via 2-HG production by the IDH1 R132 mutation.
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http://dx.doi.org/10.3892/ol.2020.12214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586285PMC
December 2020

Kyoto probe-1 reveals phenotypic differences between mouse ES cells and iTS-P cells.

Sci Rep 2020 10 22;10(1):18084. Epub 2020 Oct 22.

Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.

Kyoto probe 1 (KP-1) rapidly distinguishes between human ES/iPS (hES/iPS) cells and their differentiated cells. Recently, we generated induced tissue-specific stem cells from pancreas (iTS-P cells) using reprogramming factors and tissue-specific selection. The iTS-P cells have self-renewal potential, and subcutaneously transplanting them into immunodeficient mice did not generate teratomas. In this study, we applied KP-1 to analyze mouse ES (mES) cells and mouse iTS-P (miTS-P) cells. KP-1 completely stained mES cells in colonies, but only miTS-P cells at the edge of a colony. This difference was caused by cell type-specific expression of different ABC transporters. These finding suggest that KP-1 will be useful for distinguishing between iPS and iTS-P cells.
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http://dx.doi.org/10.1038/s41598-020-75016-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582910PMC
October 2020

Dynamin 1 is important for microtubule organization and stabilization in glomerular podocytes.

FASEB J 2020 12 17;34(12):16449-16463. Epub 2020 Oct 17.

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

Dynamin 1 is a neuronal endocytic protein that participates in vesicle formation by scission of invaginated membranes. Dynamin 1 is also expressed in the kidney; however, its physiological significance to this organ remains unknown. Here, we show that dynamin 1 is crucial for microtubule organization and stabilization in glomerular podocytes. By immunofluorescence and immunoelectron microscopy, dynamin 1 was concentrated at microtubules at primary processes in rat podocytes. By immunofluorescence of differentiated mouse podocytes (MPCs), dynamin 1 was often colocalized with microtubule bundles, which radially arranged toward periphery of expanded podocyte. In dynamin 1-depleted MPCs by RNAi, α-tubulin showed a dispersed linear filament-like localization, and microtubule bundles were rarely observed. Furthermore, dynamin 1 depletion resulted in the formation of discontinuous, short acetylated α-tubulin fragments, and the decrease of microtubule-rich protrusions. Dynamins 1 and 2 double-knockout podocytes showed dispersed acetylated α-tubulin and rare protrusions. In vitro, dynamin 1 polymerized around microtubules and cross-linked them into bundles, and increased their resistance to the disassembly-inducing reagents Ca and podophyllotoxin. In addition, overexpression and depletion of dynamin 1 in MPCs increased and decreased the nocodazole resistance of microtubules, respectively. These results suggest that dynamin 1 supports the microtubule bundle formation and participates in the stabilization of microtubules.
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http://dx.doi.org/10.1096/fj.202001240RRDOI Listing
December 2020

Nitroxoline inhibits bladder cancer progression by reversing EMT process and enhancing anti-tumor immunity.

J Cancer 2020 23;11(22):6633-6641. Epub 2020 Sep 23.

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

Nitroxoline is considered to be an effective treatment for the urinary tract infections. Recently, it has been found to be effective against several cancers. However, few studies have examined the anti-tumor activity of nitroxoline in bladder cancer. The purpose of the study was to reveal the possible mechanisms how nitroxoline inhibited bladder cancer progression. assay, we demonstrated that nitroxoline inhibited bladder cancer cell growth and migration in a concentration-related manner. Western blot analysis demonstrated that nitroxoline downregulated the expressions of epithelial mesenchymal transition (EMT)-related proteins. Furthermore, treatment with nitroxoline in the C3H/He mice bladder cancer subcutaneous model resulted in significant inhibition of tumor growth. Moreover, the percentage of myeloid-derived suppressor cells (MDSC) in peripheral blood cells significantly decreased after treatment of nitroxoline. Taken together, our results suggested that nitroxoline may be used as a potential drug for bladder cancer.
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http://dx.doi.org/10.7150/jca.47025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545671PMC
September 2020

Low-dose rituximab induction therapy is effective in immunological high-risk renal transplantation without increasing cytomegalovirus infection.

Int J Urol 2020 Dec 3;27(12):1136-1142. Epub 2020 Oct 3.

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

Objectives: To analyze the effect and impact of low-dose rituximab induction therapy on cytomegalovirus infection in living-donor renal transplantation.

Methods: A total of 92 recipients undergoing living-donor renal transplantation at Okayama University Hospital from May 2009 to August 2018 were evaluated retrospectively. Indications for preoperative rituximab (200 mg/body) were the following: (i) ABO major mismatch; (ii) ABO minor mismatch; (iii) donor-specific anti-human leukocyte antigen antibody-positive; and (iv) focal segmental glomerulosclerosis. We excluded four recipients who were followed <3 months, five who received >200 mg/body rituximab and seven who received prophylactic therapy for cytomegalovirus.

Results: There were 59 patients in the rituximab group and 17 in the non-rituximab group. Groups differed significantly in age (median age 53 vs 37 years, respectively; P = 0.04), but not in sex (male 64% vs 65%, P = 1.00), focal segmental glomerulosclerosis (3% vs 0%, P = 1.00) or percentage of cytomegalovirus-seronegative recipients of renal allografts from cytomegalovirus-seropositive donors (12% vs 18%, P = 0.68). The estimated glomerular filtration rate did not differ significantly between groups until 24 months after transplantation. Cytomegalovirus clinical symptoms (10% vs 24%, P = 0.22), including fever ≥38°C (5% vs 12%, P = 0.31) and gastrointestinal symptoms (5% vs 12%, P = 0.31), and the 5-year survival rates of death-censored graft loss (90% vs 83%, P = 0.43) did not differ significantly between groups.

Conclusions: Low-dose rituximab induction therapy is effective in immunological high-risk recipients without increasing cytomegalovirus infection in the absence of valganciclovir prophylaxis.
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http://dx.doi.org/10.1111/iju.14382DOI Listing
December 2020

Tumor suppressor REIC/Dkk-3 and its interacting protein SGTA inhibit glucocorticoid receptor to nuclear transport.

Exp Ther Med 2020 Aug 29;20(2):1739-1745. Epub 2020 May 29.

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

REIC/Dkk-3 is a tumor suppressor, and its expression is significantly downregulated in a variety of human cancer types. A previous study performed yeast two-hybrid screening and identified the small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA), known as a negative modulator of cytoplasmic androgen receptor (AR) signaling, which is a novel interacting partner of REIC/Dkk-3. The previous study also indicated that the REIC/Dkk-3 protein interferes with the dimerization of SGTA and then upregulates the AR transport and signaling in human prostate cancer PC3 cells. Since the transport of some steroid receptors to nucleus is conducted similarly by dynein motor-dependent way, the current study aimed to investigate the role of SGTA and REIC/Dkk-3 in the transport of other glucocorticoid receptors (GR). reporter assays for the cytoplasmic GR transport were performed in human prostate cancer PC3 cells and 293T cells. As for the SGTA protein, a suppressive effect on the GR transport to the nucleus was observed in the cells. As for the REIC/Dkk-3 protein, an inhibitory effect was observed for the GR transport in PC3 cells. Under the depleted condition of SGTA by short-hairpin (sh)RNA, the downregulation of GR transport by REIC/Dkk-3 was significantly enhanced compared with the non-depleted condition in PC3 cells, suggesting a compensatory role of REIC/Dkk-3 in the SGTA mediated inhibition of GR transport. The current study therefore demonstrated that SGTA inhibited the cytoplasmic transport of GR in 293T and PC3 cells, and REIC/Dkk-3 also inhibited the cytoplasmic transport of GR in PC3 cells. These results may be used to gain novel insight into the GR transport and signaling in normal and cancer cells.
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http://dx.doi.org/10.3892/etm.2020.8819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388570PMC
August 2020

Long-term ureteroscopic management of upper tract urothelial carcinoma: 28-year single-centre experience.

Jpn J Clin Oncol 2021 Jan;51(1):130-137

Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Background: Long-term survival outcomes of patients who undergo endoscopic management of non-invasive upper tract urothelial carcinoma remain uncertain. The longest mean follow-up period in previous studies was 6.1 years. This study reports the long-term outcomes of patients with upper tract urothelial carcinoma who underwent ureteroscopic ablation at a single institution over a 28-year period.

Methods: We identified all patients who underwent ureteroscopic management of upper tract urothelial carcinoma as their primary treatment at our institution between January 1991 and April 2011. Survival outcomes, including overall survival, cancer-specific survival, upper-tract recurrence-free survival and renal unit survival, were estimated using Kaplan-Meier methodology.

Results: A total of 15 patients underwent endoscopic management, with a mean age at diagnosis of 66 years. All patients underwent ureteroscopy, and biopsy-confirmed pathology was obtained. Median (range; mean) follow-up was 11.7 (2.3-20.9, 11.9) years. Upper tract recurrence occurred in 87% (n = 13) of patients. Twenty percent (n = 3) of patients proceeded to nephroureterectomy. The estimated cancer-specific survival rate was 93% at 5, 10, 15 and 20 years. Estimated overall survival rates were 86, 80, 54 and 20% at 5, 10, 15 and 20 years. Only one patient experienced cancer-specific mortality. The estimated mean and median overall survival times were 14.5 and 16.6 years, respectively. The estimated mean cancer-specific survival time was not reached.

Conclusions: Although upper tract recurrence is common, endoscopic management of non-invasive upper tract urothelial carcinoma provides a 90% cancer-specific survival rate at 20 years in selected patients.
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http://dx.doi.org/10.1093/jjco/hyaa132DOI Listing
January 2021

Internalization of AMPA-type Glutamate Receptor in the MIN6 Pancreatic β-cell Line.

Cell Struct Funct 2020 Aug 24;45(2):121-130. Epub 2020 Jun 24.

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

The activity of AMPA-type glutamate receptor is involved in insulin release from pancreatic β-cells. However, the mechanism and dynamics that underlie AMPA receptor-mediated insulin release in β-cells is largely unknown. Here, we show that AMPA induces internalization of glutamate receptor 2/3 (GluR2/3), AMPA receptor subtype, in the mouse β-cell line MIN6. Immunofluorescence experiments showed that GluR2/3 appeared as fine dots that were distributed throughout MIN6 cells. Intracellular GluR2/3 co-localized with AP2 and clathrin, markers for clathrin-coated pits and vesicles. Immunoelectron microscopy revealed that GluR2/3 was also localized at plasma membrane. Surface biotinylation and immunofluorescence measurements showed that addition of AMPA caused an approximate 1.8-fold increase in GluR2/3 internalization under low-glucose conditions. Furthermore, internalized GluR2 largely co-localized with EEA1, an early endosome marker. In addition, GluR2/3 co-immunoprecipitated with cortactin, a F-actin binding protein. Depletion of cortactin by RNAi in MIN6 cells altered the intracellular distribution of GluR2/3, suggesting that cortactin is involved in internalization of GluR2/3 in MIN6 cells. Taken together, our results suggest that pancreatic β-cells adjust the amount of AMPA-type GluR2/3 on the cell surface to regulate the receptive capability of the cell for glutamate.Key words: endocytosis, GluR2, AMPA, cortactin, MIN6.
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http://dx.doi.org/10.1247/csf.20020DOI Listing
August 2020

Dkk3/REIC, an N-glycosylated Protein, Is a Physiological Endoplasmic Reticulum Stress Inducer in the Mouse Adrenal Gland.

Acta Med Okayama 2020 Jun;74(3):199-208

Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

Dickkopf 3 (Dkk3) is a secreted protein belonging to the Dkk family and encoded by the orthologous gene of REIC. Dkk3/REIC is expressed by mouse and human adrenal glands, but the understanding of its roles in this organ is still limited. To determine the functions of Dkk3 in the mouse adrenal gland, we first identified that the mouse Dkk3 protein is N-glycosylated in the adrenal gland as well as in the brain. We performed proteome analysis on adrenal glands from Dkk3-null mice, in which exons 5 and 6 of the Dkk3 gene are deleted. Twodimensional polyacrylamide gel electrophoresis of adrenal proteins from wild-type and Dkk3-null mice revealed 5 protein spots whose intensities were altered between the 2 genotypes. Mass spectrometry analysis of these spots identified binding immunoglobulin protein (BiP), an endoplasmic reticulum (ER) chaperone. To determine whether mouse Dkk3 is involved in the unfolded protein response (UPR), we carried out a reporter assay using ER-stress responsive elements. Forced expression of Dkk3 resulted in the induction of distinct levels of reporter expression, showing the UPR initiated by the ER membrane proteins of activating transcription factor 6 (ATF6) and inositol-requring enzyme 1 (IRE1). Thus, it is possible that Dkk3 is a physiological ER stressor in the mouse adrenal gland.
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http://dx.doi.org/10.18926/AMO/59950DOI Listing
June 2020

Mutations in the C1 element of the insulin promoter lead to diabetic phenotypes in homozygous mice.

Commun Biol 2020 06 16;3(1):309. Epub 2020 Jun 16.

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.

Genome editing technologies such as CRISPR-Cas9 are widely used to establish causal associations between mutations and phenotypes. However, CRISPR-Cas9 is rarely used to analyze promoter regions. The insulin promoter region (approximately 1,000 bp) directs β cell-specific expression of insulin, which in vitro studies show is regulated by ubiquitous, as well as pancreatic, β cell-specific transcription factors. However, we are unaware of any confirmatory in vivo studies. Here, we used CRISPR-Cas9 technology to generate mice with mutations in the promoter regions of the insulin I (Ins1) and II (Ins2) genes. We generated 4 homozygous diabetic mice with 2 distinct mutations in the highly conserved C1 elements in each of the Ins1 and Ins2 promoters (3 deletions and 1 replacement in total). Remarkably, all mice with homozygous or heterozygous mutations in other loci were not diabetic. Thus, the C1 element in mice is required for Ins transcription in vivo.
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http://dx.doi.org/10.1038/s42003-020-1040-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297962PMC
June 2020

Correlation between lumbar skeletal muscle size and urinary incontinence after radical prostatectomy.

Low Urin Tract Symptoms 2020 Sep 6;12(3):245-252. Epub 2020 May 6.

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

Objectives: Urinary incontinence is a major concern after radical prostatectomy because it can decrease quality of life. The aim of the present study was to explore the effect of preoperative skeletal muscle on urinary quality of life after robot-assisted radical prostatectomy.

Methods: A total of 762 patients underwent robot-assisted radical prostatectomy. Longitudinal health-related quality of life was evaluated using the Expanded Prostate Cancer Index Composite instrument. The skeletal muscle area at the level of the third lumbar vertebra was assessed preoperatively by computed tomography and was standardized to height to obtain the skeletal muscle index. Reduced skeletal muscle size (RSMS) was defined as a skeletal muscle index ≤ 53 or ≤ 43 cm /m in patients with a body mass index (BMI) ≥25 or < 25, respectively.

Results: A total of 301 patients were included in this study, of whom 91 were classified as having RSMS (30.2%). Non-RSMS patients exhibited better urinary function at 12 months (P = .012) and better urinary continence recovery at 2 weeks and 12 months (P = .033 and P = .014, respectively) after prostatectomy compared with RSMS patients. Univariate and multivariate analyses identified preoperative RSMS as a significant and independent predictor of urinary incontinence (odds ratio = 1.77, P = .028).

Conclusions: Patients with RSMS had a lower urinary quality of life compared with non-RSMS patients after robot-assisted radical prostatectomy, and RSMS, independent of age or BMI, was predictive of postoperative urinary incontinence.
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http://dx.doi.org/10.1111/luts.12312DOI Listing
September 2020

Factors predicting pathological upgrading after prostatectomy in patients with Gleason grade group 1 prostate cancer based on opinion-matched biopsy specimens.

Mol Clin Oncol 2020 Apr 10;12(4):384-389. Epub 2020 Feb 10.

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

The present study investigated the concordance between Gleason scores assigned to prostate biopsy specimens by outside pathologists and a urological pathology expert, and determined the risk of upgrading between opinion-matched Gleason grade group (GGG) 1 biopsy specimens and radical prostatectomy specimens. Between January 2012 and May 2018, 733 patients underwent robot-assisted radical prostatectomy. Patients whose original biopsy specimens from outside hospitals were reviewed by a urological pathology expert Okayama University Hospital were included. Patients who had received neoadjuvant hormonal therapy were excluded. Logistic regression analysis was used to identify predictors of upgrading among GGG 1 diagnoses. A total of 403 patients were included in the present study. Agreement in GGG between initial and second-opinion diagnoses was present in 256 cases (63.5%). Although opinion-matched cases improved concordance between biopsy and prostatectomy specimen GGG compared with single-opinion cases (initial, 35.2%; second-opinion, 36.5%; matched, 41.4%), 71% (56/79) of cases classified as GGG 1 were upgraded after prostatectomy. Multivariate analysis revealed that prostate-specific antigen density and Prostate Imaging Reporting and Data System version 2 score were significant predictors of upgrading (odds ratio, 1.10; P=0.01; and odds ratio, 1.88; P=0.03, respectively). In conclusion, the GGG concordance rate between needle-core biopsy and radical prostatectomy specimens was higher in opinion-matched cases; however, 71% of opinion-matched GGG1 cases were upgraded after robot-assisted radical prostatectomy. Urologists should propose treatment strategies or further biopsy rather than active surveillance for patients with GGG1 and a high PSAD and/or PI-RADS score.
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http://dx.doi.org/10.3892/mco.2020.1996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057918PMC
April 2020

Promising Gene Therapy Using an Adenovirus Vector Carrying REIC/Dkk-3 Gene for the Treatment of Biliary Cancer.

Curr Gene Ther 2020 ;20(1):64-70

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.

Background: We previously demonstrated that the reduced expression in immortalized cells (REIC)/dikkopf-3 (Dkk-3) gene was downregulated in various malignant tumors, and that an adenovirus vector carrying the REIC/Dkk-3 gene, termed Ad-REIC induced cancer-selective apoptosis in pancreatic cancer and hepatocellular carcinoma.

Objective: In this study, we examined the therapeutic effects of Ad-REIC in biliary cancer using a second- generation Ad-REIC (Ad-SGE-REIC).

Methods: Human biliary cancer cell lines (G-415, TFK-1) were used in this study. The cell viability and apoptotic effect of Ad-SGE-REIC were assessed in vitro using an MTT assay and Hoechst staining. The anti-tumor effect in vivo was assessed in a mouse xenograft model. We also assessed the therapeutic effects of Ad-SGE-REIC therapy with cisplatin. Cell signaling was assessed by Western blotting.

Results: Ad-SGE-REIC reduced cell viability, and induced apoptosis in biliary cancer cell lines via the activation of the c-Jun N-terminal kinase pathway. Ad-SGE-REIC also inhibited tumor growth in a mouse xenograft model. This effect was further enhanced in combination with cisplatin.

Conclusion: Ad-SGE-REIC induced apoptosis and inhibited tumor growth in biliary cancer cells. REIC/Dkk-3 gene therapy using Ad-SGE-REIC is an attractive therapeutic tool for biliary cancer.
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http://dx.doi.org/10.2174/1566523220666200309125709DOI Listing
January 2020

Quality of Life and Mental Satisfaction Improve Slowly in Preemptive Kidney Transplantation Compared With Nonpreemptive Kidney Transplantation.

Transplant Proc 2020 Apr 4;52(3):740-747. Epub 2020 Mar 4.

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

Background And Aims: Preemptive kidney transplantation (PEKT) is recognized as the best therapy to avoid dialysis. However, it is not clear whether PEKT recipients experience an improvement in quality of life (QoL) after kidney transplantation (KT) that exceeds that of non-PEKT recipients, since PEKT recipients have not experienced the heavy burden of dialysis. The aim of this study was to compare the changes in QoL for PEKT and non-PEKT recipients following transplantation.

Methods: Patients included in this study underwent living donor KT in our hospital. We excluded patients with incomplete SF-36 scores and with factors that could affect QoL, such as complications or rejection. QoL was assessed by the Short Form 36-Item Health Survey version 2.0 preoperatively and 3 and 12 months postoperatively.

Results: Eighty-eight patients underwent living donor KT in our hospital. Twelve PEKT and 20 non-PEKT recipients were enrolled in this retrospective study. In the non-PEKT group, both the physical and mental domain scores dramatically improved from baseline at 3 months, and remained at a similar level at 12 months. In contrast, in the PEKT group, only 1 domain of the physical and mental score improved at 3 months, and the social functioning score gradually improved at 12 months. Although the mental component score showed significant improvement in the non-PEKT group, it did not change in the PEKT group.

Conclusions: The improvement of QoL after transplantation is more evident in the non-PEKT group. PEKT recipients have less mental satisfaction than non-PEKT recipients.
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http://dx.doi.org/10.1016/j.transproceed.2020.01.042DOI Listing
April 2020

Robotic Renal Autotransplantation: A Feasibility Study in a Porcine Model.

Acta Med Okayama 2020 Feb;74(1):53-58

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

We investigated the feasibility of robotic renal autotransplantation (RAT) in a porcine model to reduce invasiveness of RAT. Five pigs underwent robotic RAT using the da Vinci® robotic system. A robotic left nephrectomy was performed in all cases. Robotic RAT was performed on the left side in all but one case. Four ports were used. In 3 cases, the kidney was taken out through the GelPort® and irrigated on ice with Ringer's solution. In 2 cases, a complete intracorporeal robotic RAT was performed. An end-to-side anastomosis was performed between the renal vein and the external iliac vein and between the renal artery and the external iliac artery. Ureteroneocystostomy was also performed in 2 cases. All cases were performed robotically without open conversion. The median (IQR) console time was 3.1 (0.7) h, and the operative time was 3.8 (1.1) h. The estimated blood loss was 30 (0) ml. The warm ischemia time was 4.0 (0.2) min, and the cold ischemia time was 97 (17) min. Intracorporeal transarterial hypothermic renal perfusion was feasible in the 2 complete intracorporeal robotic RAT cases by using a perfusion catheter through a laparoscopic port. Robotic RAT has the potential to be a new minimally invasive substitute for conventional open surgery.
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http://dx.doi.org/10.18926/AMO/57953DOI Listing
February 2020

Novel cell-permeable p38-MAPK inhibitor efficiently prevents porcine islet apoptosis and improves islet graft function.

Am J Transplant 2020 05 30;20(5):1296-1308. Epub 2019 Dec 30.

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

During islet transplantation, mitogen-activated protein kinase (MAPK) p38 is preferentially activated in response to the isolation of islets and the associated inflammation. Although therapeutic effects of p38 inhibitors are expected, the clinical application of small-molecule inhibitors of p38 is not recommended because of their serious adverse effects on the liver and central nervous system. Here we designed peptides to inhibit p38, which were derived from the sites on p38 that mediate binding to proteins such as MAPK kinases. Peptide 11R-p38I significantly inhibited the activation of p38. To evaluate the effects of 11R-p38I , porcine islets were incubated with 10 µmol/L 11R-p38I or a mutant form designated 11R-mp38I . After islet transplantation, blood glucose levels reached the normoglycemic range in 58.3% and 0% of diabetic mice treated with 11R-p38I or 11R-mp38I , respectively. These data suggest that 11R-p38I inhibited islet apoptosis and improved islet function. Peptide p38I is a noncompetitive inhibitor of ATP and targets a unique docking site. Therefore, 11R-p38I specifically inhibits p38 activation, which may avoid the adverse effects that have discouraged the clinical use of small-molecule inhibitors of p38. Moreover, our methodology to design "peptide inhibitors" could be used to design other inhibitors derived from the binding sites of proteins.
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http://dx.doi.org/10.1111/ajt.15740DOI Listing
May 2020