Publications by authors named "Hiroshi Mizuno"

217 Publications

Reply: Quality and Quantity-Cultured Human Mononuclear Cells Improve Human Fat Graft Vascularization and Survival in an In Vivo Murine Experimental Model.

Plast Reconstr Surg 2021 Oct 18. Epub 2021 Oct 18.

Department of Plastic and Reconstructive Surgery Department of Regenerative Therapy Juntendo University School of Medicine Tokyo, Japan.

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http://dx.doi.org/10.1097/PRS.0000000000008543DOI Listing
October 2021

Use of Dental Impression Silicone to Fabricate Simple Surgical Guides in Mandibular Reconstruction.

J Craniofac Surg 2021 Jul 20. Epub 2021 Jul 20.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo Department of Oral and Maxillofacial Surgery, Toyooka Public Hospital, Toyooka Hyougo, Japan Department of Plastic and Reconstructive Surgery, Ghent University Hospital, Ghent, Belgium.

Background: Several recent reports have described the development and use of three-dimensional (3D) printed surgical osteotomy guides. However, these methods: are usually costly. Here, we introduce a novel method of manufacturing surgical guides built from inexpensive, easy-to-use, and sterilizable dental impression silicone.

Methods: Mandibular and fibular models were prepared using a 3D printer for 10 patients undergoing free fibula flap transfer after mandibular resection. During preoperative simulation surgery, Protesil labor, a dental silicone, was molded to the same size as the fibular models to act as surgical guides.

Results: The authors compared pre- and post-operative bone angles and bone lengths for all cases using simulation surgery models and postoperative 3D computed tomography. Mean bone angle difference was 2.6° and mean bone length difference was 1.7 mm. Cost of the dental silicone was approximately US$5/patient.

Conclusions: In our series this method allowed the surgeon to perform an accurate osteotomy, inexpensively and time-efficiently.
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http://dx.doi.org/10.1097/SCS.0000000000007878DOI Listing
July 2021

The Combination of Stromal Vascular Fraction Cells and Platelet-Rich Plasma Reduces Malondialdehyde and Nitric Oxide Levels in Deep Dermal Burn Injury.

J Inflamm Res 2021 8;14:3049-3061. Epub 2021 Jul 8.

Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia.

Introduction: Thermal burns release reactive oxygen species, which cause profound systemic and local changes. Stromal vascular fraction cells (SVFs) combined with platelet-rich plasma accelerate burn wound healing. This study investigated the effect of a combination of locally injected SVFs and PRP on malondialdehyde (MDA) and nitric oxide (NO) serum and tissue levels in a deep dermal burn model in Wistar rats.

Methods: Thirty-six adult Wistar rats weighing between 150 and 250 grams were used in this study to establish a deep dermal degree burn wound model. They were randomly divided into 4 groups: locally injected the combination SVFs and PRP, the Vaseline group, the placebo group, and healthy Wistar rats (the normal control group). MDA and NO levels in blood serum and burn wound tissue were measured at 8, 24, and 48 hours. Data were analyzed with one-way ANOVA followed by multiple comparisons tests and regression tests.

Results: Local injection of SVFs and PRP in combination affected blood MDA, tissue MDA, blood NO and tissue NO levels, with reductions of 0.257µmol/L, 0.427 µmol/L, 21.78nmol/mg, and 23.777nmol/mg, respectively. Injection of SVFs and PRP in combination reduced tissue MDA levels by 1.282 times, NO blood levels by 2.305, and NO tissue levels by 2.377 times compared to Vaseline application.

Conclusion: The combination of SVFs and PRP undeniably reduced the MDA and NO levels in blood and tissue compared to those in the Vaseline and placebo groups. The injection of these two preparations in combination inhibited the local and systemic stress oxidative response, as illustrated by the decreased MDA and NO levels in blood serum and tissue.
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http://dx.doi.org/10.2147/JIR.S318055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275197PMC
July 2021

A Case of Presumed Dyskeratosis Congenita Causing Severe Retinal Vascular Occlusion.

Case Rep Ophthalmol 2021 May-Aug;12(2):344-349. Epub 2021 May 7.

Department of Ophthalmology, Osaka Medical College, Takatsuki-City, Japan.

Dyskeratosis congenita (DKC) is a rare, multisystem, bone marrow failure disease characterized by abnormalities such as in the skin, mucosa, nervous system, and lungs. Here we report a rare case of presumed DKC causing total retinal detachment in the right eye and severe peripheral retinal vascular occlusion in the left eye. A 3-year-old boy was presented with vitreous hemorrhage and total retinal detachment in the right eye and was scheduled to undergo vitreous surgery in the right eye and detailed ophthalmologic examination of the left eye under general anesthesia. Since a systemic examination revealed anemia and marked thrombocytopenia, he underwent a detailed pediatric examination. Although genetic testing revealed no significant pathologic mutations, the presence of shortened telomere length and other clinical findings suggested the possibility of DKC. His right eye had severe proliferative vitreoretinopathy, and retinal reattachment was not achieved with vitreous surgery, thus resulting in phthisis bulbi. The left eye showed a wide retinal avascular area in the temporal retina, retinal neovascularization, and hard exudates on fluorescein fundus angiography and was treated with laser photocoagulation using a binocular indirect ophthalmoscopic photocoagulator. Following laser surgery, the new blood vessels regressed, and the visual acuity was maintained at 1.0. The findings in this rare case indicate that DKC can cause severe retinal vascular occlusion, thus leading to vitreous hemorrhage and retinal detachment. Therefore, early detection with fundus examination and early treatment with photocoagulation are important.
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http://dx.doi.org/10.1159/000513484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136308PMC
May 2021

Use of Sponge-Foam Inserts in Compression Bandaging of Non-Healing Venous Leg Ulcers.

Ann Vasc Dis 2021 Mar;14(1):46-51

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Sapporo, Hokkaido, Japan.

Venous leg ulcers (VLUs) caused by chronic venous insufficiency are difficult to treat. Outcomes after compression therapy and the current standard of care often used in conjunction with other options vary widely. We examined the effects of foam inserts on sub-bandage pressures in patients with VLUs and compared use of foam inserts in elastic and inelastic compression bandaging. Six patients (≥20 years old) with VLUs and skin perfusion pressure >40 mmHg were included. Each patient underwent weekly treatment regimens of debridement, dressing changes, and dual sponge-insert application followed by elastic (n=3) or inelastic (n=3) compression bandaging. The median resting sub-bandage pressures of the ulcer beds, wound sizes, and healing percentages were recorded. Wound beds were biopsied before and after treatment for histological assessment. Nine healthy volunteers served as controls during preliminary testing. With proper sub-bandage pressures (>35 mmHg), the average healing time was 88.0±66 days, which was shorter than anticipated (i.e., ≥6 months). Combining large and local sponge-foam inserts increased sub-bandage pressures regardless of the compression bandage selected, with marked improvements seen in deeper wounds. Layering one or two sponge-foam inserts beneath compression bandages facilitates uniform and optimal wound-bed pressure, which accelerates the healing of VLUs.
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http://dx.doi.org/10.3400/avd.oa.20-00159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991709PMC
March 2021

Ex vivo conditioning of peripheral blood mononuclear cells of diabetic patients promotes vasculogenic wound healing.

Stem Cells Transl Med 2021 Jun 18;10(6):895-909. Epub 2021 Feb 18.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

The quality and quantity of endothelial progenitor cells (EPCs) are impaired in patients with diabetes mellitus patients, leading to reduced tissue repair during autologous EPC therapy. This study aimed to address the limitations of the previously described serum-free Quantity and Quality Control Culture System (QQc) using CD34+ cells by investigating the therapeutic potential of a novel mononuclear cell (MNC)-QQ. MNCs were isolated from 50 mL of peripheral blood of patients with diabetes mellitus and healthy volunteers (n = 13 each) and subjected to QQc for 7 days in serum-free expansion media with VEGF, Flt-3 ligand, TPO, IL-6, and SCF. The vascular regeneration capability of MNC-QQ cells pre- or post-QQc was evaluated with an EPC colony-forming assay, FACS, EPC culture, tube formation assay, and quantitative real time PCR. For in vivo assessment, 1 × 10 pre- and post-MNC-QQc cells from diabetic donors were injected into a murine wound-healing model using Balb/c nude mice. The percentage of wound closure and angio-vasculogenesis was then assessed. This study revealed vasculogenic, anti-inflammatory, and wound-healing effects of MNC-QQ therapy in both in vitro and in vivo models. This system addresses the low efficiency and efficacy of the current naïve MNC therapy for wound-healing in diabetic patients. As this technique requires a simple blood draw, isolation, and peripheral blood MNC suspension culture for only a week, it can be used as a simple and effective outpatient-based vascular and regenerative therapy for patients with diabetes mellitus.
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http://dx.doi.org/10.1002/sctm.20-0309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133343PMC
June 2021

Medicine at mass gatherings: current progress of preparedness of emergency medical services and disaster medical response during 2020 Tokyo Olympic and Paralympic Games from the perspective of the Academic Consortium (AC2020).

Acute Med Surg 2021 Jan-Dec;8(1):e626. Epub 2021 Feb 2.

Japan Pediatric Society Tokyo Japan.

Mass gatherings are events characterized by "the concentration of people at a specific location for a specific purpose over a set period of time that have the potential to strain the planning and response resources of the host country or community." Previous reports showed that, as a result of the concentration of people in the limited area, injury and illness occurred due to several factors. The response plan should aim to provide timely medical care to the patients and to reduce the burden on emergency hospitals, and to maintain a daily emergency medical services system for residents of the local area. Although a mass gathering event will place a significant burden on the local health-care system, it can provide the opportunity for long-term benefits of public health-care and improvement of daily medical service systems after the end of the event. The next Olympic and Paralympic Games will be held in Tokyo, during which mass gatherings will occur on a daily basis in the context of the coronavirus disease (COVID-19) epidemic. The Academic Consortium on Emergency Medical Services and Disaster Medical Response Plan during the Tokyo Olympic and Paralympic Games in 2020 (AC2020) was launched 2016, consisting of 28 academic societies in Japan, it has released statements based on assessments of medical risk and publishing guidelines and manuals on its website. This paper outlines the issues and countermeasures for emergency and disaster medical care related to the holding of this big event, focusing on the activities of the academic consortium.
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http://dx.doi.org/10.1002/ams2.626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852170PMC
February 2021

Quality and Quantity-Cultured Human Mononuclear Cells Improve Human Fat Graft Vascularization and Survival in an In Vivo Murine Experimental Model.

Plast Reconstr Surg 2021 02;147(2):373-385

From the Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine; and the Department of Plastic and Reconstructive Surgery, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel.

Background: Fat graft ischemia impedes us from having satisfying long-term results. The quality and quantity culture is a 1-week cell culture that increases the vasculogenic potential of peripheral blood mononuclear cells (PBMNC). This in vivo murine model investigates whether enrichment with quality and quantity-cultured human mononuclear cells (MNC-QQ) improves the vascularization in the human fat graft and whether this decreases the tissue loss.

Methods: Human adipose tissue, PBMNC, MNC-QQ, and stromal vascular fraction were prepared. First, PBMNC, MNC-QQ, and stromal vascular fraction were compared in vitro for vasculogenic potential by endothelial progenitor cell colony-forming and culture assays. Second, 0.25-g fat grafts were created with 1 × 106 PBMNC (n = 16), 1 × 106 MNC-QQ (n = 16), 1 × 106 stromal vascular fraction (n = 16), or phosphate-buffered saline as control (n = 16) before grafting in BALB/c nude mice. Grafts were analyzed for weight persistence, vessel formation by CD31 immunohistochemistry, and angiogenic markers by quantitative polymerase chain reaction.

Results: MNC-QQ develop more definitive endothelial progenitor cell colonies and more functional endothelial progenitor cells compared to PBMNC and stromal vascular fraction. Weight persistence after 7 weeks was significantly higher in grafts with MNC-QQ (89.8 ± 3.5 percent) or stromal vascular fraction (90.1 ± 4.2 percent) compared with control (70.4 ± 6.3 percent; p < 0.05). MNC-QQ-enriched grafts had the highest vessel density (96.6 ± 6.5 vessels/mm2; control, 70.4 ± 5.6 vessels/mm2; p < 0.05). MNC-QQ exerted a direct vasculogenic effect through vascular integration and a potential paracrine vascular endothelial growth factor-mediated effect.

Conclusion: Quality and quantity-cultured human mononuclear cells containing endothelial progenitor cells stimulate fat graft vascularization and enhance graft survival in a rodent recipient.
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http://dx.doi.org/10.1097/PRS.0000000000007580DOI Listing
February 2021

Essential structural and experimental descriptors for bulk and grain boundary conductivities of Li solid electrolytes.

Sci Technol Adv Mater 2020 Oct 19;21(1):712-725. Epub 2020 Oct 19.

Center for Materials Research by Information Integration (CMI2), Research and Services Division of Materials Data and Integrated System (Madis), National Institute for Materials Science (NIMS), Tsukuba, Japan.

We present a computational approach for identifying the important descriptors of the ionic conductivities of lithium solid electrolytes. Our approach discriminates the factors of both bulk and grain boundary conductivities, which have been rarely reported. The effects of the interrelated structural (e.g. grain size, phase), material (e.g. Li ratio), chemical (e.g. electronegativity, polarizability) and experimental (e.g. sintering temperature, synthesis method) properties on the bulk and grain boundary conductivities are investigated via machine learning. The data are trained using the bulk and grain boundary conductivities of Li solid conductors at room temperature. The important descriptors are elucidated by their feature importance and predictive performances, as determined by a nonlinear XGBoost algorithm: (i) the experimental descriptors of sintering conditions are significant for both bulk and grain boundary, (ii) the material descriptors of Li site occupancy and Li ratio are the prior descriptors for bulk, (iii) the density and unit cell volume are the prior structural descriptors while the polarizability and electronegativity are the prior chemical descriptors for grain boundary, (iv) the grain size provides physical insights such as the thermodynamic condition and should be considered for determining grain boundary conductance in solid polycrystalline ionic conductors.
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http://dx.doi.org/10.1080/14686996.2020.1824985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594868PMC
October 2020

Involvement of the Retinal Pigment Epithelium in the Development of Retinal Lattice Degeneration.

Int J Mol Sci 2020 Oct 5;21(19). Epub 2020 Oct 5.

Department of Ophthalmology, Osaka Medical College, Takatsuki-City, Osaka 569-8686, Japan.

Lattice degeneration involves thinning of the retina that occurs over time. Here we performed an immunohistological study of tissue sections of human peripheral retinal lattice degeneration to investigate if retinal pigment epithelium (RPE) cells are involved in the pathogenesis of this condition. In two cases of retinal detachment with a large tear that underwent vitreous surgery, retinal lattice degeneration tissue specimens were collected during surgery. In the obtained specimens, both whole mounts and horizontal section slices were prepared, and immunostaining was then performed with hematoxylin and antibodies against glial fibrillary acidic protein (GFAP), RPE-specific protein 65 kDa (RPE65), pan-cytokeratin (pan-CK), and CK18. Hematoxylin staining showed no nuclei in the center of the degenerative lesion, thus suggesting the possibility of the occurrence of apoptosis. In the degenerative lesion specimens, GFAP staining was observed in the center, RPE65 staining was observed in the slightly peripheral region, and pan-CK staining was observed in all areas. However, no obvious CK18 staining was observed. In a monkey retina used as the control specimen of a normal healthy retina, no RPE65 or pan-CK staining was observed in the neural retina. Our findings suggest that migration, proliferation, and differentiation of RPE cells might be involved in the repair of retinal lattice degeneration.
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http://dx.doi.org/10.3390/ijms21197347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583762PMC
October 2020

Correction of serum potassium with sodium zirconium cyclosilicate in Japanese patients with hyperkalemia: a randomized, dose-response, phase 2/3 study.

Clin Exp Nephrol 2020 Dec 10;24(12):1144-1153. Epub 2020 Aug 10.

Research and Development, AstraZeneca K.K, 1-8-3, Marunouchi, Chiyoda-ku, Tokyo, 100-0005, Japan.

Background: Sodium zirconium cyclosilicate (SZC) is an oral potassium binder approved to treat hyperkalemia in adults in a number of countries, including Japan.

Methods: This phase 2/3, randomized, double-blind, placebo-controlled, dose-response study (ClinicalTrials.gov: NCT03127644) was designed to determine the efficacy and safety of SZC in Japanese adults with hyperkalemia. Patients with serum potassium (sK) concentrations ≥ 5.1- ≤ 6.5 mmol/L were randomized 1:1:1 to SZC 5 g, SZC 10 g, or placebo three times daily for 48 h (six doses total). The primary efficacy endpoint was the exponential rate of change in sK over 48 h. The proportion of patients with normokalemia (sK 3.5-5.0 mmol/L) at 48 h and adverse events (AEs) were also evaluated.

Results: Overall, 103 patients (mean age, 73.2 years; range 50-89 years) received SZC 5 g (n = 34), SZC 10 g (n = 36), or placebo (n = 33). The exponential rate of sK change from 0 to 48 h versus placebo was - 0.00261 (SZC 5 g) and - 0.00496 (SZC 10 g; both P < 0.0001). At 48 h, the proportions of patients with normokalemia were 85.3%, 91.7%, and 15.2% with SZC 5 g, SZC 10 g, and placebo, respectively. No serious AEs were reported. Hypokalemia (sK  < 3.5 mmol/L) occurred in two patients in the SZC 10 g group; normokalemia was re-established within 6 days and no treatment-related AEs were reported.

Conclusion: SZC is effective and well tolerated in Japanese patients with hyperkalemia.
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http://dx.doi.org/10.1007/s10157-020-01937-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599176PMC
December 2020

Split-skin Paddle Anterolateral Thigh Flap for Reconstruction of Giant Dermatofibrosarcoma Protuberans in Groin.

Plast Reconstr Surg Glob Open 2019 Dec 12;7(12):e2528. Epub 2019 Dec 12.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Dermatofibrosarcoma protuberans (DFSP) is a slow-growing superficial sarcoma. Due to its high late local recurrence, thin skin graft is usually recommended for reconstruction after resection of the tumor. In this report, we present a case of giant DFSP in the groin region of young woman. Reconstruction of large groin defect after DFSP resection was performed by "split-skin paddle anterolateral thigh flap" instead of skin graft considering that the patient was a 29-year-old woman. This method enabled the primary closure of the donor site and provided the positive functional and esthetic outcomes. In the present case, the surgical scar is less conspicuous and the patient can climb and descend stairs without any trouble at 4 years after the surgery. With careful monitoring of the tumor recurrence, this technique may become a reliable reconstruction option for patients with large groin defect after resection of the malignant tumor.
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http://dx.doi.org/10.1097/GOX.0000000000002528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288881PMC
December 2019

A massively parallel barcoded sequencing pipeline enables generation of the first ORFeome and interactome map for rice.

Proc Natl Acad Sci U S A 2020 05 12;117(21):11836-11842. Epub 2020 May 12.

Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853;

Systematic mappings of protein interactome networks have provided invaluable functional information for numerous model organisms. Here we develop CR-mediated inkage of barcoded dapters o nucleic acid lements for uencing (PLATE-seq) that serves as a general tool to rapidly sequence thousands of DNA elements. We validate its utility by generating the ORFeome for covering 2,300 genes and constructing a high-quality protein-protein interactome map consisting of 322 interactions between 289 proteins, expanding the known interactions in rice by roughly 50%. Our work paves the way for high-throughput profiling of protein-protein interactions in a wide range of organisms.
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http://dx.doi.org/10.1073/pnas.1918068117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260977PMC
May 2020

Evolutionary dynamics and impacts of chromosome regions carrying R-gene clusters in rice.

Sci Rep 2020 01 21;10(1):872. Epub 2020 Jan 21.

Institute of Crop Science (NICS), National Agriculture and Food Research Organization, 1-2, Ohwashi, Tsukuba, Ibaraki, 305-8634, Japan.

To elucidate R-gene evolution, we compared the genomic compositions and structures of chromosome regions carrying R-gene clusters among cultivated and wild rice species. Map-based sequencing and gene annotation of orthologous genomic regions (1.2 to 1.9 Mb) close to the terminal end of the long arm of rice chromosome 11 revealed R-gene clusters within six cultivated and ancestral wild rice accessions. NBS-LRR R-genes were much more abundant in Asian cultivated rice (O. sativa L.) than in its ancestors, indicating that homologs of functional genes involved in the same pathway likely increase in number because of tandem duplication of chromosomal segments and were selected during cultivation. Phylogenetic analysis using amino acid sequences indicated that homologs of paired Pikm1-Pikm2 (NBS-LRR) genes conferring rice-blast resistance were likely conserved among all cultivated and wild rice species we examined, and the homolog of Xa3/Xa26 (LRR-RLK) conferring bacterial blight resistance was lacking only in Kasalath.
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http://dx.doi.org/10.1038/s41598-020-57729-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972905PMC
January 2020

Oncoplastic Lower Eyelid Reconstruction Analysis.

J Craniofac Surg 2019 Nov-Dec;30(8):2396-2400

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine.

Background: Oncoplastic lower eyelid reconstruction is a challenging task due to the complicated structure of the eyelid and requirement of high operative accuracy. Poorly treated defects result in ectropion and ptosis which may lead to keratitis and corneal ulceration. Previous related studies do not include a detailed comparison of the common reconstructive methods of the lower eyelid in terms of results and complication rates.

Objective: The authors aim to demonstrate whether the choice of reconstruction affects the aesthetic and functional outcome of oncoplastic lower eyelid reconstruction.

Methods & Materials: The authors performed a 10-year retrospective review of all oncoplastic lower eyelid reconstructions carried out in our hospital. Information on patient background, diagnosis and the choice of reconstructive method were evaluated. Postoperative photographs of each patient were then subjectively evaluated for color match, cosmesis, quality of shape, symmetry, and overall appearance. The authors hypothesized that the outcome is related to the main trajectory of the flap. Patients treated with local flaps of horizontal and vertical trajectories were then compared in terms of outcome and complication rates.

Results: Reconstructions based on a horizontal trajectory compared with a vertical trajectory resulted with lower rates of ectropion and ptosis occurrence. The results were statistically significant.
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http://dx.doi.org/10.1097/SCS.0000000000005639DOI Listing
January 2020

Potential Advantages of Using Three-Dimensional Exoscope for Microvascular Anastomosis in Free Flap Transfer.

Plast Reconstr Surg 2019 10;144(4):726e-727e

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1097/PRS.0000000000006088DOI Listing
October 2019

Keloid patients have higher peripheral blood endothelial progenitor cell counts and CD34 cells with normal vasculogenic and angiogenic function that overexpress vascular endothelial growth factor and interleukin-8.

Int J Dermatol 2019 Dec 9;58(12):1398-1405. Epub 2019 Jul 9.

Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan.

Background: One suggested reason for aberrant wound healing in keloid scars is chronic inflammation of the dermis. We hypothesized that excessive blood vessel formation and high capillary density in keloid tissue is caused by dysfunction of endothelial progenitor cells.

Methods: We compared the number of circulating endothelial progenitor cells and vasculogenic and angiogenic capacity, as well as secretory function, of circulating CD34 cells in keloid patients and healthy individuals.

Results: Compared to mononuclear cell cultures from healthy donors, cultures of peripheral blood mononuclear cells obtained from keloid patients showed a more than twofold increase in the number of peripheral blood EPCs (fibronectin-adhering cells that phagocytized acetylated low-density lipoprotein and bound Ulex europaeus agglutinin-I lectin). However, there was no difference in colony-forming ability and participation in in vitro angiogenesis between circulating CD34 cells isolated from keloid patients and healthy individuals. This means that circulating CD34 /endothelial progenitor cells in keloid patients have normal vasculogenic and angiogenic function. However, CD34 cells derived from keloid patients demonstrated a more than sevenfold expression of the interleukin-8 gene and a more than fivefold expression of the vascular endothelial growth factor gene than CD34 cells derived from healthy individuals.

Conclusions: These results support the role of vascular endothelial growth factor and interleukin-8 in increased recruitment of endothelial progenitor cells in keloid patients.
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http://dx.doi.org/10.1111/ijd.14575DOI Listing
December 2019

Exposure-response analysis of drug-induced QT interval prolongation in telemetered monkeys for translational prediction to human.

J Pharmacol Toxicol Methods 2019 Sep - Oct;99:106606. Epub 2019 Jun 27.

Japanese Safety Pharmacology Society (JSPS), Saitama 355-0071, Japan.

Introduction: The preclinical in vivo assay for QT prolongation is critical for predicting torsadogenic risk, but still difficult to extrapolate to humans. This study ran preclinical tests in cynomolgus monkeys on seven QT reference drugs containing the drugs used in the IQ-CSRC clinical trial and applied exposure-response (ER) analysis to the data to investigate the potential for translational information on the QT effect.

Methods: In each of six participating facilities in the J-ICET project, telemetered monkeys were monitored for 24 h following administration of vehicle or 3 doses of test drugs, and pharmacokinetic profiles at the same doses were evaluated separately. An individual rate-corrected QT interval (QTca) was derived and the vehicle-adjusted change in QTca from baseline (∆∆QTca) was calculated. Then the relationship of concentration to QT effect was evaluated by ER analysis.

Results: For QT-positive drugs in the IQ-CSRC study (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and levofloxacin, the slope of the total concentration-QTca effect was significantly positive, and the QT-prolonging effect, taken as the upper bound of the confidence interval for predicted ∆∆QTca, was confirmed to exceed 10 ms. The ER slope of the negative drug levocetirizine was not significantly positive and the QTca effect was below 10 ms at observed peak exposure.

Discussion: Preclinical QT assessment in cynomolgus monkeys combined with ER analysis could identify the small QT effect induced by several QT drugs consistently with the outcomes in humans. Thus, the ER method should be regarded as useful for translational prediction of QT effects in humans.
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http://dx.doi.org/10.1016/j.vascn.2019.106606DOI Listing
June 2019

Quality and Quantity-Cultured Murine Endothelial Progenitor Cells Increase Vascularization and Decrease Fibrosis in the Fat Graft.

Plast Reconstr Surg 2019 Apr;143(4):744e-755e

From the Plastic and Reconstructive Surgery Department, Juntendo University School of Medicine; and the Plastic and Reconstructive Surgery Department, Universitair Ziekenhuis Brussel (University Hospital Brussels), Vrije Universiteit Brussel.

Background: Fat grafting has become a valuable technique for soft-tissue reconstruction; however, long-lasting success depends on several determinants. An early blood supply to the transplanted adipocytes is important to prevent ischemia. The recently developed quality and quantity (QQ) culture increases the vasculogenic potential of endothelial progenitor cells. The authors used a murine fat grafting model to address the hypothesis that QQ-cultured endothelial progenitor cells stimulate the establishment of a blood vessel network and increase graft success.

Methods: c-KitSca-1Lin (KSL) cells were isolated as endothelial progenitor cell precursors from C57BL/6 mice. Adipose tissue was grafted with QQ-cultured KSL cells (QQKSL group), uncultured KSL cells (KSL group), adipose-derived stem cells (ASC group), and a combination (QQKSL+ASC group), and compared to a control group. Five and 10 weeks later, grafts were weighed, histologic and immunohistochemical parameters were evaluated, and gene expression was quantified by quantitative polymerase chain reaction.

Results: The highest vessel density was observed in the combined QQKSL+ASC group (68.0 ± 4.3/mm; p < 0.001) and the QQKSL group (53.9 ± 3.0/mm; p < 0.001). QQKSL cells were engrafted in proximity to the graft vasculature. QQKSL cells decreased the fibrosis percentage (13.8 ± 1.8 percent; p < 0.05). The combined QQKSL+ASC group (22.4 ± 1.8/mm; p < 0.001) showed the fewest local inflammation units. A significant up-regulation of platelet-derived growth factor and adiponectin expression was observed in the QQKSL group and QQKSL+ASC group. Graft weight persistence was not significantly different between groups.

Conclusions: Supplementing fat grafts with quality and quantity-cultured endothelial progenitor cells improves graft quality by stimulating vascularization. The increased vessel density is associated with less fibrosis, less inflammation, and better adipose tissue integrity. Enriching fat grafts with QQ-cultured endothelial progenitor cells is a potential solution to their clinical shortcomings.
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http://dx.doi.org/10.1097/PRS.0000000000005439DOI Listing
April 2019

Mammary Analogue Secretory Carcinoma Arising in the Parotid Gland of Child.

Plast Reconstr Surg Glob Open 2018 Dec 13;6(12):e2059. Epub 2018 Dec 13.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Mammary analogue secretory carcinoma (MASC) of salivary glands is a newly recognized tumor entity. We report a child who was initially diagnosed with lymphangioma and referred to our institute for sclerotherapy, only to find out that the tumor was in fact MASC after excision. This case of MASC is in a 7-year-old boy, the youngest case so far reported. He referred to his primary care physician with a infra-auricular swelling, and it was diagnosed as lymphatic malformation he was referred to our institution for sclerotherapy. For Doppler and ultrasound magnetic resonance imaging, there was a distinct cystic lesion with a heterogeneous solid lesion inside. Minimally invasive treatment such as sclerotherapy was thought to be more desirable due to a pediatric case, the risk of postoperative facial paralysis and scar. However, even the successful treatment of cystic lesion with sclerotherapy, solid lesion of the tumor could be remained without pathological findings. Otolaryngologist also thought the importance of pathological diagnosis, and we finally chose surgical excision. The tumor was ultimately diagnosed as MASC considering histological and genetic findings. For child case, we tend to treat patient less invasively, and it might bring a risk of MASC being incorrectly treated nonsurgically such as with sclerotherapy. This could lead to tumor progression and wider radical excision at last. We believe that histological diagnosis should become the priority in similar cases of mixed solid and cystic tumors to avoid incorrect treatment, and we need to choose surgical excision by understanding the character of salivary gland tumor occurring in childhood.
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http://dx.doi.org/10.1097/GOX.0000000000002059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326613PMC
December 2018

Quantitative Analysis of Change in Intracranial Volume After Posterior Cranial Vault Distraction and Frontal Orbital Advancement/Remodeling.

J Craniofac Surg 2019 Jan;30(1):23-27

Department of Plastic and Reconstructive Surgery, Teikyo University, Tokyo, Japan.

Introduction: Patients with craniosynostosis with shortened occipitofrontal diameter are mainly treated with posterior cranial vault distraction osteogenesis (PVDO) in our institution. If further intracranial volume (ICV) expansion is needed, additional treatment with frontal orbital advancement (FOA) is done. On the contrary, frontal orbital remodeling (FOR) is done for better aesthetic results. In this study, post-treatment ICV changes in patients with craniosynostosis treated with these methods have been investigated.

Methods: Patients who underwent FOA or FOR in addition to PVDO at Juntendo University Hospital between 2011 and 2017 were reviewed for patient characteristics and pre/postoperative ICV measurements using 3-dimensional computed tomography scans.

Results: Nine patients aged from 5 months to 6 years 8 months at the time of PVDO were included. For PVDO, the ICV change was 113 to 328 mL, and the enlargement ratio of ICV was 109% to 152%. Two patients were further operated with FOA while the remaining 7 with FOR. With FOA, ICV change was 73 to 138 mL, while enlargement ratio of ICV was 107% to 114%. With FOR, ICV change was 3 to 45 mL (mean 20 mL), while enlargement ratio of ICV was 100% to 103%.

Conclusion: The PVDO is our first line of treatment for ICV expansion and posterior cranial fossa decompression in patients with severe craniosynostosis. The FOA is performed if extra ICV increase is necessary. This approach seems to enable larger ICV expansions compared with other conventional methods. The FOR should be reserved for patients in whom adequate ICV levels are achieved with PVDO yet additional frontal reshaping is necessary.
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http://dx.doi.org/10.1097/SCS.0000000000004948DOI Listing
January 2019

Effectiveness of endothelial progenitor cell culture under microgravity for improved angiogenic potential.

Sci Rep 2018 09 24;8(1):14239. Epub 2018 Sep 24.

Department of Plastic and Reconstructive Surgery, School of Medicine, Juntendo University, Tokyo, Japan.

Endothelial progenitor cell (EPC) transplantation is beneficial for ischemic diseases such as critical limb ischemia and ischemic heart disease. The scarcity of functional EPCs in adults is a limiting factor for EPC transplantation therapy. The quality and quantity culture (QQc) system is an effective ex vivo method for enhancing the number and angiogenic potential of EPCs. Further, microgravity environments have been shown to enhance the functional potential of stem cells. We therefore hypothesized that cells cultured with QQc under microgravity may have enhanced functionality. We cultured human peripheral blood mononuclear cells using QQc under normal (E), microgravity (MG), or microgravity followed by normal (ME) conditions and found that ME resulted in the most significant increase in CD34+ and double positive Dil-Ac-LDL-FITC-Ulex-Lectin cells, both EPC markers. Furthermore, angiogenic potential was determined by an EPC-colony forming assay. While numbers of primitive EPC-colony forming units (pEPC-CFU) did not change, numbers of definitive EPC-CFU colonies increased most under ME conditions. Gene-expression profiling also identified increases in angiogenic factors, including vascular endothelial growth factor, under MG and ME conditions. Thus, QQc along with ME conditions could be an efficient system for significantly enhancing the number and angiogenic potential of EPCs.
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http://dx.doi.org/10.1038/s41598-018-32073-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155294PMC
September 2018

Human peripheral blood mononuclear cells enriched in endothelial progenitor cells via quality and quantity controlled culture accelerate vascularization and wound healing in a porcine wound model.

Cell Transplant 2018 07 5;27(7):1068-1079. Epub 2018 Jul 5.

1 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

The transplantation of endothelial progenitor cells (EPCs) is used to promote wound angiogenesis. In patients with chronic wounds and accompanying morbidities, EPCs are often compromised in number and function. To overcome these limitations, we previously developed a quality and quantity controlled (QQ) culture system to enrich peripheral blood mononuclear cells (PBMNCs) in EPCs. To evaluate the wound healing efficacy of mononuclear cells (MNCs) harvested after QQ culture (QQMNCs), preclinical studies were performed on large animals. MNCs harvested from the blood of healthy human subjects were cultured in the presence of angiogenic cytokines and growth factors in a serum-free medium for 7 days. A total of 5 × 10 QQMNCs per full-thickness skin defect or control saline was injected into wounds induced in cyclosporine-immunosuppressed pigs. EPC colony-forming assays revealed a significantly higher number of definitive (partially differentiated) EPC colony-forming units in QQMNCs. Flow cytometry evaluation of QQMNC surface markers showed enrichment of CD34 and CD133 stem cell populations, significant reduction in CCR2 cell percentages, and a greater than 10-fold increase in the percentage of anti-inflammatory M2-type macrophages (CD206 cells) compared with PBMNCs. Wounds treated with QQMNCs had a significantly higher closure rate. Wounds were harvested, frozen, and sectioned at day 21 postoperatively. Hematoxylin and eosin staining revealed that the epithelization of QQMNC-treated wounds was more advanced than in controls. Treated wounds developed granulation tissue with more mature collagen and larger capillary networks. CD31 and human mitochondrial co-staining confirmed the presence of differentiated human cells within newly formed vessels. Real-time polymerase chain reaction (PCR) showed upregulation of interleukin 6 (IL-6), IL-10, and IL-4 in the wound bed, suggesting paracrine activity of the transplanted QQMNCs. Our data demonstrate for the first time that QQ culture of MNCs obtained from a small amount of peripheral blood yields vasculogenic and therapeutic cells effective in wound healing.
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http://dx.doi.org/10.1177/0963689718780307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158547PMC
July 2018

Human Peripheral Blood Mononuclear Cells Incubated in Vasculogenic Conditioning Medium Dramatically Improve Ischemia/Reperfusion Acute Kidney Injury in Mice.

Cell Transplant 2018 03 8;27(3):520-530. Epub 2018 May 8.

5 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Ochanomizu, Japan.

Acute kidney injury (AKI) is a major clinical problem that still has no established treatment. We investigated the efficacy of cultured human peripheral blood mononuclear cells (PBMNCs) for AKI. Ischemia/reperfusion injury (IRI) was used to induce AKI in male nonobese diabetic (NOD/severe combined immunodeficiency) mice aged 7 to 8 wk. PBMNCs were isolated from healthy volunteers and were subjected to quality and quantity controlled (QQc) culture for 7 d in medium containing stem cell factor, thrombopoietin, Flt-3 ligand, vascular endothelial growth factor, and interleukin 6. IRI-induced mice were divided into 3 groups and administered (1) 1 × 10 PBMNCs after QQc culture (QQc PBMNCs group), (2) 1 × 10 PBMNCs without QQc culture (non-QQc PBMNCs group), or (3) vehicle without PBMNCs (IRI control group). PBMNCs were injected via the tail vein 24 h after induction of IRI, followed by assessment of renal function, histological changes, and homing of injected cells. Blood urea nitrogen and serum creatinine (Cr) 72 h after induction of IRI in the QQc PBMNCs group dramatically improved compared with those in the IRI control and the non-QQc PBMNCs groups, accompanied by the improvement of tubular damages. Interstitial fibrosis 14 d after induction of IRI was also significantly improved in the QQc PBMNCs group compared with the other groups. The renoprotective effect noted in the QQc PBMNCs group was accompanied by reduction of peritubular capillary loss. The change of PBMNCs' population (increase of CD34+ cells, CD133+ cells, and CD206+ cells) and increased endothelial progenitor cell colony-forming potential by QQc culture might be one of the beneficial mechanisms for restoring AKI. In conclusion, an injection of human QQc PBMNCs 24 h after induction of IRI dramatically improved AKI in mice.
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http://dx.doi.org/10.1177/0963689717753186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038042PMC
March 2018

Bone Regeneration with a Combination of Adipose-Derived Stem Cells and Platelet-Rich Plasma.

Methods Mol Biol 2018 ;1773:261-272

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Mesenchymal stem cells (MSCs) have the potential to directly differentiate into osteogenic cells and efficiently regenerate bone tissue. Adipose-derived stem cells (ASCs) have the potential to differentiate into an osteogenic lineage, too. In addition, ASCs can be readily harvested in large numbers with low donor-site morbidity. Meanwhile, recent reports have demonstrated that platelet-rich plasma (PRP) contains a variety of growth factors and may be a powerful biological autologous cocktail of growth factors for tissue engineering.We have shown that ASC/PRP admixture had dramatic effects on bone regeneration in a rat calvarial defect model, not only through the osteogenic potential of ASCs, but also through the release of cytokines by platelets in PRP, which, in turn, support ASCs.In this chapter, we introduce the bone regeneration using a combination of ASCs and PRP in a rat calvarial defect model.
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http://dx.doi.org/10.1007/978-1-4939-7799-4_20DOI Listing
June 2019

A Case of Retinal Detachment with Unique Optical Coherence Tomography Findings after Gamma Knife® Radiosurgery Treatment for Choroidal Melanoma.

Case Rep Ophthalmol 2018 Jan-Apr;9(1):17-23. Epub 2018 Jan 5.

Department of Ophthalmology, Osaka Medical College, Takatsuki, Japan.

Purpose: To report a case of retinal detachment with unique optical coherence tomography (OCT) findings after Gamma Knife® (GK; Elekta Instrument AB, Stockholm, Sweden) treatment for choroidal melanoma (CM).

Case Report: A 48-year-old woman underwent GK therapy for CM in her right eye from the macula to the temporal side. While the tumor subsequently shrank, the patient developed radiation retinopathy, which was treated with laser photocoagulation. The tumor lesions later subsided; however, her visual acuity (VA) decreased 8 years after the initial treatment. Although the tumor lesions in the right eye had become scarred, a bullous retinal detachment with fixed folds occurred in the superior-nasal quadrants. OCT examination revealed a preretinal membrane, vitreoretinal traction, and an inner retinal break; however, no outer retinal break was clearly detectable. MRI scans showed no increase in tumorous lesions, and I-IMP SPECT imaging showed no photon accumulation. Thus, it was determined that there was no tumor activity. The corrected VA in her right eye was light perception, and it was determined that there was no indication for vitreous surgery.

Conclusion: In this case, an inner retinal break was formed by the vitreoretinal traction around the scarred tumor and radiation retinopathy, thus suggesting the possibility of the development of a rhegmatogenous retinal detachment presumably complicated with an outer retinal break.
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http://dx.doi.org/10.1159/000485317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892324PMC
January 2018

Quality-Quantity Control Culture Enhances Vasculogenesis and Wound Healing Efficacy of Human Diabetic Peripheral Blood CD34+ Cells.

Stem Cells Transl Med 2018 05 24;7(5):428-438. Epub 2018 Mar 24.

Department of Basic Clinical Science, Division of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.

Autologous endothelial progenitor cell (EPC) therapy is commonly used to stimulate angiogenesis in ischemic repair and wound healing. However, low total numbers and functional deficits of EPCs make autologous EPC therapy ineffective in diabetes. Currently, no known ex vivo culture techniques can expand and/or ameliorate the functional deficits of EPCs for clinical usage. Recently, we showed that a quality-quantity culture (QQc) system restores the vasculogenic and wound-healing efficacy of murine diabetic EPCs. To validate these results and elucidate the mechanism in a translational study, we evaluated the efficacy of this QQc system to restore the vasculogenic potential of diabetic human peripheral blood (PB) CD34+ cells. CD34+ cells purified from PB of diabetic and healthy patients were subjected to QQc. Gene expression, vascular regeneration, and expression of cytokines and paracrine mediators were analyzed. Pre- or post-QQc diabetic human PB-CD34+ cells were transplanted into wounded BALB/c nude mice and streptozotocin-induced diabetic mice to assess functional efficacy. Post-QQc diabetic human PB-CD34+ cell therapy significantly accelerated wound closure, re-epithelialization, and angiogenesis. The higher therapeutic efficacy of post-QQc diabetic human PB-CD34+ cells was attributed to increased differentiation ability of diabetic CD34+ cells, direct vasculogenesis, and enhanced expression of angiogenic factors and wound-healing genes. Thus, QQc can significantly enhance the therapeutic efficacy of human PB-CD34+ cells in diabetic wounds, overcoming the inherent limitation of autologous cell therapy in diabetic patients, and could be useful for treatment of not only wounds but also other ischemic diseases. Stem Cells Translational Medicine 2018;7:428-438.
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http://dx.doi.org/10.1002/sctm.17-0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905232PMC
May 2018

Root lodging is a physical stress that changes gene expression from sucrose accumulation to degradation in sorghum.

BMC Plant Biol 2018 01 3;18(1). Epub 2018 Jan 3.

Institute of Crop Science (NICS), National Agriculture and Food Research Organization, 2-1-2, Kannondai, Tsukuba, Ibaraki, 305-8518, Japan.

Background: Sorghum (Sorghum bicolor L.) is used as a raw material for biofuels because it accumulates sugars at high levels in the stem. Lodging of sorghum occurs when the soil is wet and very high winds blow across the field. In root lodging, the roots are pulled loose from the soil, causing the plant to fall over. Lodging reduces the yield of nonstructural carbohydrates. It is not yet clear which genes show changes in expression when sorghum falls over. We compared whole-gene expression in the mature stems of intact and lodged sorghum plants, with a focus on comparisons from the perspective of differences in sugar accumulation or degradation.

Results: Lodging decreased sucrose content, starch content, and ratio of sucrose to total sugars in the stems of the sorghum cultivar SIL-05. Particular paralogs of SWEET and TMT family genes, which encode sucrose or hexose transporters, or both, were significantly highly expressed in intact or lodged sorghum stems. In intact stems, genes encoding the glucose-6-phosphate translocator, aquaporins, and enzymes involved in photosynthesis and starch synthesis were highly expressed. In lodged sorghum stems, expression of genes associated with sucrose or starch degradation or energy production was increased. Notably, expression of genes encoding enzymes catalyzing irreversible reactions and associated with the first steps of these metabolic pathways (e.g. INV, SUS, and hexokinase- and fructokinase-encoding genes) was significantly increased by lodging. Expression of SUT, SPS, and SPP was almost the same in intact and lodged sorghum.

Conclusions: Specific paralogs of sucrose-associated genes involved in metabolic pathways and in membrane transport were expressed in the stems of sorghum SIL-05 at the full-ripe stage. Root lodging drastically changed the expression of these genes from sucrose accumulation to degradation. The changes in gene expression resulted in decreases in sugar content and in the proportion of sucrose to hexoses in the stems of lodged plants.
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http://dx.doi.org/10.1186/s12870-017-1218-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751775PMC
January 2018

Current status of bone regeneration using adipose-derived stem cells.

Histol Histopathol 2018 Jul 2;33(7):619-627. Epub 2017 Nov 2.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Many bone regeneration therapies have been developed for clinical use and have variable outcomes and serious limitations. The goal of bone regeneration is to repair a bone defect in a stable and durable manner. Cellular strategies play an important role in bone tissue engineering. Clinical factors important for successful bone regeneration are the recruitment of cells to the defect site and the production of a suitable extracellular matrix consistent with bone tissues. Adipose-derived stem cells (ASCs) can be obtained in large quantities with little donor site morbidity or patient discomfort. They are multipotent somatic stem cells and have a strong potential to differentiate and secrete growth factors. In this review, we discuss the osteogenic potential of ASCs with/without several types of scaffolds in vivo and their clinical application for bone regeneration.
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http://dx.doi.org/10.14670/HH-11-942DOI Listing
July 2018

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice.

PLoS One 2017 23;12(5):e0178232. Epub 2017 May 23.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Persistent inflammatory environment and abnormal macrophage activation are characteristics of chronic diabetic wounds. Here, we attempted to characterize the differences in macrophage activation and temporal variations in cytokine expression in diabetic and non-diabetic wounds, with a focus on interleukin (IL)-6 mRNA expression and the p38 MAPK and PI3K/Akt signaling pathways. Cutaneous wound closure, CD68- and arginase-1 (Arg-1)-expressing macrophages, and cytokine mRNA expression were examined in non-diabetic and streptozotocin-induced type 1 diabetic mice at different time points after injury. The effect of IL-6 on p38 MAPK and Akt phosphorylation was investigated, and an in vitro scratch assay was performed to determine the role of IL-6 in primary skin fibroblast migration. Before injury, mRNA expression levels of the inflammatory markers iNOS, IL-6, and TNF-α were higher in diabetic mice; however, IL-6 expression was significantly lower 6 h post injury in diabetic wounds than that in non-diabetic wounds. Non-diabetic wounds exhibited increased p38 MAPK and Akt phosphorylation; however, no such increase was found in diabetic wounds. In fibroblasts from non-diabetic mice, IL-6 increased the phosphorylation of p38 MAPK and levels of its downstream factor CREB, and also significantly increased Akt phosphorylation and levels of its upstream factor P13K. These effects of IL-6 were not detected in fibroblasts derived from the diabetic mice. In scratch assays, IL-6 stimulated the migration of primary cultured skin fibroblasts from the non-diabetic mice, and the inhibition of p38 MAPK was found to markedly suppress IL-6-stimulated fibroblast migration. These findings underscore the critical differences between diabetic and non-diabetic wounds in terms of macrophage activation, cytokine mRNA expression profile, and involvement of the IL-6-stimulated p38 MAPK-Akt signaling pathway. Aberrant macrophage activation and abnormalities in the cytokine mRNA expression profile during different phases of wound healing should be addressed when designing effective therapeutic modalities for refractory diabetic wounds.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178232PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441644PMC
September 2017
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