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Retrospective and prospective studies of high resolution cross sectional echocardiograms were undertaken in order to establish an ultrasonic method for the non-invasive estimation of degeneration and fibrosis of the endomyocardium in cases of cardiomyopathy. When the echocardiograms of the ventricular wall were compared with the histological specimens intense abnormal echoes were seen at the sites of myocardial degeneration and fibrosis of the ventricular wall. The abnormal echoes classified into five types: types I, II, III-1, III-2, and III-3. Type I and type III-1 echoes were the strongest followed by those of types II and III-2, and then those of type III-3. The intensity of the abnormal echoes was 5-20 decibels stronger than that from intact tissue and was closely related to the consistency and density of the diseased tissue. These findings strongly suggest that the boundary between degeneration or fibrosis and the intact normal myocardium was the source of the abnormal myocardial echoes and that the extent and the pattern of the distribution of the sites of degeneration and fibrosis in the myocardium were reflected in the echo patterns. Thus the tissue characteristics of the sites of degeneration or fibrosis of the myocardium may be determined non-invasively by measuring the echo intensity. [ABSTRACT FROM PUBLISHER]

Induction of immunoglobulin secretion by human colostrum was investigated using human peripheral blood lymphocytes (PBL) and Epstein-Barr virus transformed human B lymphoblastoid cells. Stimulation of the cells with colostrum induced IgA plaque forming cells but neither IgG nor IgM plaque forming cells, indicating the occurrence of IgA specific helper factor (αHF) in human colostrum. αHF activity was eluted into fractions with an apparent molecular weight of about 80 k D by gel filtration, and with a PI range of 5-8 to 6-2 by chromatofocusing, IgA secreted by PBL stimulated with αHF had a similar molecular weight distribution to that of IgA in human colostrum From these results a hypothesis is proposed; IgA-committed B cells in the mammary gland differentiate to plasma cells producing dimeric IgA after stimulation by αHF so that the dominant immunoglobulin in human colostrum is IgA. [ABSTRACT FROM AUTHOR]

Abstract Background Safe and efficient gene transfer systems are needed for tissue engineering. We have developed an apatite composite layer including the bone morphogenetic protein-2 (BMP-2) gene and fibronectin (FB), and we evaluated its ability to induce bone formation. Methods An apatite composite layer was evaluated to determine the efficiency of gene transfer to cells cultured on it. Cells were cultured on a composite layer including the BMP-2 gene and FB, and BMP-2 gene expression, BMP-2 protein concentrations, alkaline phosphatase (ALP) activity, and osteocalcin (OC) concentrations were measured. A bone defect on the cranium of rats was treated with hydroxyapatite (HAP)-coated ceramic buttons with the apatite composite layer including the BMP-2 gene and FB (HAP-BMP-FB). The tissue concentration of BMP-2, bone formation, and the expression levels of the BMP-2, ALP, and OC genes were all quantified. Results The apatite composite layer provided more efficient gene transfer for the cultured cells than an apatite composite layer without FB. The BMP-2 concentration was approximately 100~600 pg/mL in the cell-culture medium. Culturing the cells on the apatite composite layer for 27 days increased ALP activity and OC concentrations. In animal experiments, the tissue concentrations of BMP-2 were over 100 pg/mg in the HAP-BMP-FB group and approximately 50 pg/mg in the control groups. Eight weeks later, bone formation was more enhanced in the HAP-BMP-FB group than in the control groups. In the tissues surrounding the HAP button, the gene expression levels of ALP and OC increased. Conclusion The BMP-2 gene-FB-apatite composite layer might be useful for bone engineering.

Background: The most problematic complication of external fixation is infection at the pin insertion site. Technology that improves the adhesion of the external fixation pin to the skin, subcutaneous tissue, and bone may prevent infection at the pin site. The purpose of this study is to formulate a calcium phosphate-fibroblast growth factor (Cp-FGF) coating on a stainless-steel external fixation pin and to verify its effectiveness in reducing infection at the pin site and its possible influence on bone fixation in animal experiments. Methods: We compared stainless-steel screws without coating (SS group; n = 32), those with a calcium phosphate coating (Cp group; n = 30), those with a Cp-FGF coating (FGF group; n = 32), and those with a Cp-FGF coating having enhanced biological activity (FGF+ group; n = 32) in male Japanese white domesticated rabbits. Screws were inserted percutaneously into the bilateral proximal tibial diaphysis of the rabbits and implanted for 4 weeks. Screws and periscrew tissue were observed postoperatively for qualitatively assessing infection. Results: Infection assessment by gross findings after 4 weeks (at screw removal) showed no significant differences between the groups. Histopathological evaluation of soft tissue infection and bone tissue infection showed no significant differences between the groups for either soft tissue or bone tissue. Since neither the FGF+ group nor the FGF group showed anti-infective effects, the biological activity of FGF is not the only determining factor. We compared SEM, XRD, coating detaching test, sustained release test, and bioassay to examine physicochemical properties among the coatings but found no sufficient differences. Conclusions: It is suggested that improving the tissue adhesion to and/or biocompatibility of pins is also important to improve the in vivo performance of Cp-FGF-coated external fixation pins.

Background: The distribution of anti-factor Xa activity (AXA) in patients with nonvalvular atrial fibrillation (NVAF) taking edoxaban 15 mg has not been fully elucidated., Methods and Results: The trough and peak AXA were measured in 19 NVAF patients taking edoxaban 15 mg. We compared these results with those in patients taking edoxaban 30 mg. The peak AXA differed significantly between the 15 mg and the 30 mg groups (0.74 ± 0.40 IU/mL vs. 1.25 ± 0.48 IU/mL, respectively; p  < 0.0001)., Conclusions: Peak but trough AXA in the patients receiving edoxaban 15 mg were significantly lower than those in patients receiving edoxaban 30 mg., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Author(s). Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Angiogenesis and vascular endothelial growth factor (VEGF) are involved in osteoarthritis (OA). We previously reported the inhibitory effect of bevacizumab in a rabbit model of OA. In the current study, we investigated the effects of lenvatinib, an angiogenesis inhibitor targeting the VEGF and fibroblast growth factor receptors, on synovitis, osteophyte formation, and cartilage degeneration in a rabbit OA model. Posttraumatic OA was induced by anterior cruciate ligament transection (ACLT) on one knee of each rabbit. Rabbits were placed into four groups according to the following lenvatinib doses: untreated control ( n = 12), L0.3: 0.3 mg/kg/day ( n = 15), L1.0: 1.0 mg/kg/day ( n = 14), and L3.0: 3.0 mg/kg/day ( n = 13) groups. We evaluated limb pain using the weight distribution ratio measured with an incapacitance tester, macroscopic osteophyte formation, and femoral condyle synovium and cartilage histology. For cartilage evaluation, the following distal sites of the femur were evaluated separately: femoral-tibial (FT), femoral-patellar (FP), and femoral corner (between FP and FT). The weight distribution ratio at 12 weeks after surgery was higher in the L0.3 and L1.0 groups than in the control group. Osteophyte formation and synovitis scores were significantly lower in the L0.3, L1.0, and L3.0 groups than in the control group. The Osteoarthritis Research Society International scores of the FT, corner, and FP sites in the L0.3 group were lower than in the control group. The cartilage thickness ratio at the FT and corner sites was significantly lower in the L0.3 group than in the control group. Krenn's grading system of cartilage synovitis showed that all lenvatinib-administered groups had significantly lower scores than the control group. MMP3 expression level in cartilage tissue was significantly lower in the L3.0 group compared with the other three groups. ADAMTS5 expression was lower in the L3.0 group compared with the control and L0.3 groups. Oral administration of lenvatinib inhibited synovitis, osteophyte formation, and cartilage degeneration and reduced pain in a rabbit ACLT model. Lenvatinib is an oral VEGF inhibitor that is easier to administer than other VEGF inhibitors and may have potential as a treatment of posttraumatic OA.

Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect by one-shot vaccination. This strategy is based on the size-dependent immunostimulation mechanism of mesoporous silica particles. Hollow mesoporous silica (HMS) nanoparticles enhance the antigen uptake with dendritic cells around the immunization site in vivo. In contrast, hierarchically porous silica (HPS) microparticles prolong cancer antigen retention and release in vivo. The size tuning of the mesoporous silica adjuvant prepared by combining both nanoparticles and microparticles demonstrates the immunological properties of both components and has a long-term anti-tumor effect after one-shot vaccination. One-shot vaccination with HMS-HPS-ovalbumin (OVA)-Poly IC (PIC, a TLR3 agonist) increases CD4 + T cell, CD8 + T cell, and CD86 + cell populations in draining lymph nodes even 4 months after vaccination, as well as effector memory CD8 + T cell and tumor-specific tetramer + CD8 + T cell populations in splenocytes. The increases in the numbers of effector memory CD8 + T cells and tumor-specific tetramer + CD8 + T cells indicate that the one-shot vaccination with HMS-HPS-OVA-PIC achieved the longest survival time after a challenge with E.G7-OVA cells among all groups. The size tuning of the mesoporous silica adjuvant shows promise for one-shot vaccination that mimics multiple clinical vaccinations in future cancer immunoadjuvant development. This study may have important implications in the long-term vaccine design of one-shot vaccinations.

Recent in vitro experiments showed that combined treatment with MHY1485, a low-molecular-weight compound, and X-ray irradiation significantly increased apoptosis and senescence in tumor cells, which was associated with oxidative stress, endoplasmic reticulum (ER) stress and p21 stabilization, compared to radiation treatment alone. However, evidence for MHY1485 treatment-mediated suppression of tumor growth in animals is still lacking. Furthermore, it has been shown that ER stress enhances immunogenic cell death (ICD) in tumor cells, as it can exert a favorable influence on the anti-cancer immune system. In the present study, we examined whether co-treatment of MHY1485 and X-ray irradiation induces ICD and in vivo tumor growth suppression using the CT26 and Lewis lung carcinoma murine tumor cell lines. We found that MHY1485 + X-ray treatment promotes ICD more effectively than X-ray treatment alone. MHY1485 suppresses tumor growth in vivo under co-treatment with X-rays and increases INF-γ, tumor necrosis factor, interleukin-2 and interleukin-12 levels in the spleen as well as the presence of CD8+ cells in the tumor. The results suggest that MHY1485 treatment leads to the conversion of irradiated tumors into effective vaccines. Thus, MHY1485 is a promising lead compound for use in combination with radiotherapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Several combined procedures have been reported for treating recurrent patellofemoral instability (RPI) with various types and severity of morphological abnormalities, but none have identified absolute threshold values as indications for surgery. We performed medial patellofemoral ligament (MPFL) reconstruction combined with a modified Elmslie-Trillat (ET) procedure on 24 knees (10 male and 11 female patients) to treat RPI with morphological abnormalities corresponding to elevated tibial tubercle-trochlear groove (TT-TG) distance, significant patella alta, and trochlear dysplasia. The inclusion criteria were RPI with morphological abnormalities corresponding to one or more of the following: sulcus angle > 160 degrees, trochlear dysplasia of Dejour classification C or D, Caton-Deschamps index > 1.5, lateral shift ratio > 50%, congruence angle > 15 degrees, or TT-TG distance > 20 mm, including habitual dislocation of the patella. Skeletally immature patients and those with congenital dislocation of the patella were excluded. The Kujala score, International Knee Documentation Committee subjective score, Knee Injury and Osteoarthritis Outcome score (KOOS), and each item of the KOOS improved significantly after surgery. Patellar apprehension sign was present preoperatively in all cases, but all disappeared postoperatively. No instance of postoperative redislocation was observed. On radiographic examination, the mean Q angle, tilting angle, lateral shift ratio, congruence angle, Caton-Deschamps index, Insall-Salvati index, and TT-TG distance improved significantly after surgery. There were no significant differences in sulcus angle after surgery. These results suggest MPFL reconstruction combined with a modified ET procedure provides satisfactory outcomes based on radiological and clinical evaluations for RPI with morphological abnormalities corresponding to elevated TT-TG distance, significant patella alta, and trochlear dysplasia., Competing Interests: M.S. reports grants from Japan Agency for Medical Research and Development and personal fees from CellSeed, Inc., outside the submitted work., (Thieme. All rights reserved.)

Introduction: The efficacy of catheter ablation in patients with low cardiac function has been previously reported; however, only a few studies have included mid-range ejection fraction (mrEF). This study aimed to evaluate the efficacy and safety of atrial fibrillation (AF) ablation in patients with left ventricular ejection fraction (LVEF) < 50%., Methods: This study retrospectively analyzed 79 patients (reduced ejection fraction [rEF]/mrEF, 38/41; paroxysmal/persistent, 37/42; heart failure hospitalizations within one year before ablation, 36 [45.6%]) who underwent the first ablation procedure at our hospital from April 2017 to December 2021. Radiofrequency ablation and cryoablation were performed for 69 and 10 patients, respectively., Results: Complications included pacemaker implantation for postoperative sick sinus syndrome in one patient and inguinal hematoma in one patient. Regarding efficacy, there were significant postoperative improvements in echocardiographic data, blood test values, and diuretic use. After a mean follow-up of 60 months, 86.1% patients had no AF recurrence. There were 9 heart failure hospitalizations (11.4%) and 5 all-cause deaths (6.3%); no significant differences were found between the rEF and mrEF groups. No significant predictors of AF recurrence were found in preoperative patient characteristics., Conclusion: AF ablation in patients with LVEF <50% significantly improved cardiac and renal functions with few complications, resulting in a high non-recurrence rate and reduced heart failure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Indian Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.)

To solve the instrument loosening problem, we developed a fibroblast growth factor-2-calcium phosphate composite layer as a novel coating material to improve screw fixation strength. The primary aim of the present study was to demonstrate the safety and feasibility of screws coated with the FGF-2-calcium phosphate composite layer for posterior instrumented surgery of the cervical spine. The trial design was a single-arm, open-label, safety and feasibility study. Patients receiving fusion of the cervical spine from C2 (or C3) to C7 (or T1) were recruited. The primary endpoint to confirm safety was any screw-related adverse events. Seven patients who underwent posterior fusion surgery of the cervical spine were enrolled in the present study. The coated pedicle screws were inserted bilaterally into the lowest instrumented vertebrae. There was only one severe adverse event unrelated with the coated screw. Three out of the fourteen coated screws showed loosening. The present results prove the safety and feasibility of pedicle screws coated with the FGF-2-calcium phosphate composite layer for fusion surgery in the cervical spine. This is the first step to apply this novel surface coating in the field of spine surgery.

Background: Vessel injuries during total knee arthroplasty or high tibial osteotomy are rare but have serious complications. This study aimed to analyze the running position of the popliteal artery (PA) and branching level of the anterior tibial artery (ATA), using magnetic resonance imaging (MRI). This analysis might be helpful in avoiding unnecessary vessel injury., Methods: In total, 105 patients (41 men and 64 women), whose running position of the PA and branching level of the ATA could be detected by preoperative MRI, were included in this study. We configured zones A, B, C, and D to be 5-10, 15-20, 25-30 and 35-40 mm distal from the lateral tibial plateau in the axial view, respectively. First, the distance between the posterior cortex of the tibia and anterior border of the PA was measured. Second, the PA position from the medial border of the tibia was measured. This measured value was divided by the transverse diameter of the tibia, and multiplied by 100 to obtain the PA position from the medial border of the tibia. Third, the branching level of ATA was measured from the joint line. Subsequently, each value was compared between men (the M group) and women (the W group)., Results: The distance between the posterior cortex of the tibia and the anterior border of the PA was 5.5 ± 1.9, 10.4 ± 2.4, 12.5 ± 2.3 and 12.5 ± 2.3 (mm; mean ± SD) in zones A, B, C, and D, respectively. Comparing both groups, this distance was significantly larger (more separated posteriorly) in zones C and D in the M group. The PA position from the medial border of the tibia was 51.7 ± 6.5, 52.7 ± 8.2, 56.7 ± 10.5 and 66.8 ± 14 (%; mean ± SD) in zones A, B, C, and D, respectively. On comparing the two groups, this position was significantly larger (more laterally shifted) in zone D in the W group. The branching level of the ATA was not detected within 40 mm distal to the joint line in 92 patients (87.6%). However, it was detected within 40 mm (mean 32.5 mm; range 20-38) in 12 patients (11.4%). Among them, 11 were women. Only one woman had an aberrant branching pattern: the ATA bifurcated at the joint level., Conclusion: The PA positioned closest at the joint level, gradually separated and shifted laterally towards the distal side. The distance between the posterior cortex of the tibia and the anterior border of the PA was closer in women than in men in zones C and D. Although a difference of 2 mm is small, the risk of PA injury can be considered to be higher in women than in men. Furthermore, ATA injury is also a concern during retraction of the tibialis anterior muscle posteriorly, and the descending cut of the tibial tuberosity, particularly in women., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Asia Pacific Knee, Arthroscopy and Sports Medicine Society. Published by Elsevier (Singapore) Pte Ltd.)

Orthopedic and dental implants coated with fibroblast growth factor-2 (FGF-2)-calcium phosphate composite layers promote dermis formation, bone formation, and angiogenesis because of the biological activity of FGF-2. Enhancing the biological activity of FGF-2 in the composite layers is important for its wider application in orthopedics and dentistry. This study incorporated low-molecular-weight heparin (LMWH) into the FGF-2-calcium phosphate composite layers and clarified the enhancing effects of LMWH on the biological activity of FGF-2 in the composite layers in vitro. LMWH-FGF-2-calcium phosphate composite layers were successfully formed on zirconia in supersaturated calcium phosphate solutions. The composite layers comprised continuous and macroscopically homogeneous layers and particles smaller than 500 nm in size composed of amorphous calcium phosphate. The amounts of Ca and P deposited on zirconia remained almost unchanged with the addition of LMWH under the presence of FGF-2 in the supersaturated calcium phosphate solution. The LMWH in the supersaturated calcium phosphate solution increased the stability of FGF-2 in the solution and the amount of FGF-2 in the composite layers. The LMWH in the composite layers increased the mitogenic and endothelial tube-forming activities of FGF-2, and FGF-2 activity of inducing osteogenic differentiation gene expression pattern in the composite layers. Our results indicate that the enhanced biological activity of FGF-2 in the LMWH-FGF-2-calcium phosphate composite layers is attributed to an LMWH-mediated increase in the amount of FGF-2, which maintains its biological activity in the supersaturated calcium phosphate solution and the composite layers. The LMWH-FGF-2-calcium phosphate composite layer is a promising coating for orthopedic and dental implants. STATEMENT OF SIGNIFICANCE: Orthopedic and dental implants coated with fibroblast growth factor-2 (FGF-2)-calcium phosphate composite layers promote dermis formation, bone formation, and angiogenesis because of the biological activity of FGF-2. Enhancing the biological activity of FGF-2 in the layers is important for wider its application in orthopedics and dentistry. This study demonstrates the enhancing effects of low-molecular-weight heparin (LMWH) contained within LMWH-FGF-2-calcium phosphate composite layers on the biological activity of FGF-2 in vitro. Our results indicate that the enhanced biological activity of FGF-2 within the composite layers arises from an LMWH-mediated increase in the amount of FGF-2, which maintains its biological activity in the LMWH-FGF-2-calcium phosphate composite layers and supersaturated calcium phosphate solutions used for coating the composite layers., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022. Published by Elsevier Ltd.)

Immune checkpoint inhibitors elicit durable tumor regression in multiple types of tumor, but may induce potential side effects with low response rates in many tumors. Herein, to increase the therapeutic efficacy of immune checkpoint inhibitors, a hollow mesoporous silica (HMS) nanosphere-based cancer vaccine was combined with an immune checkpoint inhibitor, anti-programmed death-ligand 1 (anti-PD-L1) antibody. The HMS nanospheres function as adjuvants that promote dendritic cell activation and antigen cross-presentation. Mice immunized with the HMS-based cancer vaccine show suppressed tumor growth with increased tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-2 (IL-2) levels in their spleens compared with those without HMS-based cancer vaccine. Moreover, the HMS-based cancer vaccine synergistically acts with the anti-PD-L1 antibody on the tumor. The combination of an HMS-based cancer vaccine and an antibody markedly decreases the required dose of the immune checkpoint inhibitor. Mice locally administered with the HMS-based cancer vaccine and 1/8 dose of a standard anti-PD-L1 antibody (25 µg/mouse) show comparable anti-tumor effect and significantly increased CD4 + and CD8 + T cell populations, compared with those systemically immunized with the standard anti-PD-L1 antibody done at 200 µg/mouse. Our work presents a promising cancer treatment strategy of combining an immune checkpoint inhibitor with an HMS-based cancer vaccine. STATEMENT OF SIGNIFICANCE: The clinical benefits of checkpoint blockade therapy rekindle the hope of cancer immunotherapy. However, objective response rates in checkpoint blockade therapy remain at about 10-40% owing to multiple immunosuppressive factors. To solve these problems, herein, a hollow mesoporous silica (HMS) nanosphere-based cancer vaccine was combined with an immune checkpoint inhibitor, anti-PD-L1 antibody. The HMS-based cancer vaccine synergistically acts with the anti-PD-L1 antibody on the tumor. Mice locally administered with the HMS-based cancer vaccine and 1/8 dose of a standard anti-PD-L1 antibody (25 µg/mouse) show comparable anti-tumor effect and significantly increased CD4 + and CD8 + T cell populations, compared with those systemically immunized with the standard anti-PD-L1 antibody done at 200 µg/mouse. Our work presents a promising cancer treatment strategy of combining an immune checkpoint inhibitor with an HMS-based cancer vaccine., Competing Interests: Declaration of Competing Interest Xiupeng Wang, Atsuo Ito, Yu Sogo and Tadao Ohno are inventors of Patent JP-6868862-B2. This work was supported in part by the grant from Cell-Medicine, Inc., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Ionizing radiation exposure affects the redox state in vivo. Recently, whole-blood antioxidant capacity (WBAC) has been reported to decrease in a dose-dependent manner after acute total body irradiation (TBI). However, changes in WBAC after localized and chronic irradiations have not been reported. This study analyzed changes to WBAC in mice after either localized irradiation (irradiation of the left hind leg only) or chronic TBI using the i-STrap method. Leg-localized irradiation exerted limited effects on WBAC, while WBAC decreased in a dose rate-dependent manner after TBI. Further, the WBAC reached the minimum value in a shorter period at a smaller dose rate. Our results suggest that changes in WBAC do not directly reflect absorbed dose, but may reflect radiation-induced biological damage at the systemic level. This study will contribute to the understanding of radiation-induced injuries and diseases, and will facilitate the establishment of biomarkers for radiation exposure., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The mammalian target of rapamycin (mTOR) is a sensor of nutrient status and plays an important role in cell growth and metabolism. Although inhibition of mTOR signaling promotes tumor cell death and several mTOR inhibitors have been used clinically, recent reports have shown that co-treatment with MHY1485, an mTOR activator, enhances the anti-cancer effects of anti-PD-1 antibody and 5-fluorouracil. However, it remains unclear whether MHY1485 treatment alters the effects of radiation on tumor cells. In this study, the radiosensitizing effects of MHY1485 were investigated using murine CT26 and LLC cell lines. We examined mTOR signaling, tumor cell growth, colony formation, apoptosis, senescence, oxidative stress, p21 accumulation and endoplasmic reticulum (ER) stress levels in cells treated with MHY1485 and radiation, either alone or together. We found that MHY1485 treatment inhibited growth and colony formation in both cell lines under irradiation and no-irradiation conditions, results that were not fully consistent with MHY1485's known role in activating mTOR signaling. Furthermore, we found that combined treatment with MHY1485 and radiation significantly increased apoptosis and senescence in tumor cells in association with oxidative stress, ER stress and p21 stabilization, compared to radiation treatment alone. Our results suggested that MHY1485 enhances the radiosensitivity of tumor cells by a mechanism that may differ from MHY1485's role in mTOR activation., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Mesoporous silica (MS) particles have been explored for various healthcare applications, but universal data about their safety and/or toxicity are yet to be well-established for clinical purposes. Information about general toxicity of hollow MS (HMS) particles and about immunotoxicity of MS particles are significantly lacked. Therefore, acute toxicity and immunotoxicity of HMS particles were experimentally evaluated. A systematic and objective literature study was parallelly performed to analyze the published in vivo toxicity of MS particles. Lethal acute toxicity of MS particles is likely to arise from their physical action after intravenous and intraperitoneal administrations, and only rarely observed after subcutaneous administration. No clear relationship was identified between physicochemical properties of MS particles and lethality as well as maximum tolerated dose with some exceptions. At sub-lethal doses, MS particles tend to accumulate mainly in lung, liver, and spleen. The HMS particles showed lower inflammation-inducing ability than polyinosinic-polycytidylic acid and almost the same allergy-inducing ability as Alum. Finally, the universal lowest observed adverse effect levels were determined as 0.45, 0.81, and 4.1 mg/kg (human equivalent dose) for intravenous, intraperitoneal, and subcutaneous administration of MS particles, respectively. These results could be helpful for determining an appropriate MS particle dose in clinical study., (© 2021. The Author(s).)

The phase transformation from soluble calcium phosphates to less-soluble hydroxyapatite (HAP) is a thermodynamically natural route. This process is irreversible, and effective use of poorly reactive HAP to repair teeth that have no cellular metabolism remains challenging. However, this thermodynamically controlled transformation may apparently be reversed through the fast nucleation and growth of metastable phases, leading to a reactive HAP surface. Here, the assembled HAP-nanorod phase is demonstrated to change into the metastable octacalcium phosphate (OCP) phase in a calcium phosphate solution containing 0.8 ppm fluoride. Grown OCPs display parallel surface streaks and their 11¯0 and 00l (l: odd) electron-diffraction spots are often not visible. The streaked, elongated OCP gradually grows into large plates with flat surfaces that exhibit an intense11¯0 spot. Crystal-structure models reveal that the unique epitaxial overgrowth of OCP on HAP occurs since both materials share coherent {100} faces, resulting in the distinctive disappearance of 11¯0 and 00l OCP spots. A polysynthetic twin model that reliably explains this disappearance is proposed for the growth of OCP. This apparent reverse phase transformation produces hybrid calcium phosphates consisting of HAP cores and highly reactive outer OCP layers that are promising for the repair of dentin caries. STATEMENT OF SIGNIFICANCE: This paper demonstrates important and interesting finding regarding formation of calcium phosphates in relation to their crystal structures. We first show that hydroxyapatite (HAP), the major constituent of human teeth and bone, can reversely change to its precursor, octacalcium phosphate (OCP), contrary to thermodynamic-stability rule. This apparent reverse phase transformation occurs through sharing the coherent {100} faces of both materials under controlled fluoride concentration. Nanoscale similarity of two crystal surfaces enables structurally shared epitaxial overgrowth of OCP on HAP aided by faster growth rate of OCP than that of HAP. This reaction produces hybrid crystal consisting of outer OCP and core HAP, that has not been known before and is able to be applied to dentin caries repair., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Ionizing radiation exposure may not only cause acute radiation syndrome, but also an increased risk of late effects. It has been hypothesized that induction of chronic oxidative stress mediates the late effects of ionizing radiation. However, only a few reports have analyzed changes in long-term antioxidant capacity after irradiation in vivo. Our previous study demonstrated changes in whole-blood antioxidant capacity and red blood cell (RBC) glutathione levels within 50 days after total body irradiation (TBI). In this study, seven-week-old, male, C57BL/6J mice exposed to total body irradiation by X-ray and changes in whole-blood antioxidant capacity and RBC glutathione levels at ≥ 100 days after TBI were investigated. Whole-blood antioxidant capacity was chronically decreased in the 5-Gy group. The RBC reduced glutathione (GSH) level and the GSH/oxidative glutathione (GSSG) ratio were chronically decreased after ≥ 1 Gy of TBI. Interestingly, the complete blood counts (CBC) changed less with 1-Gy exposure, suggesting that GSH and the GSH/GSSG ratio were more sensitive radiation exposure markers than whole-blood antioxidant capacity and CBC counts. It has been reported that GSH depletion is one of the triggers leading to cataracts, hypertension, and atherosclerosis, and these diseases are also known as radiation-induced late effects. The present findings further suggest that chronic antioxidant reduction may contribute to the pathogenesis of late radiation effects.

Background: Implants coated with fibroblast growth factor-2 (FGF-2)-apatite composite layers were previously reported to enhance soft-tissue formation, bone formation, and angiogenesis around the implants owing to the biological activity of FGF-2. However, it is unclear whether the chemistries of the material and surface of implants have some impact on the retention of the biological activity of FGF-2 in FGF-2-apatite composite layers on them. Since magnitude of the impact should be evaluated for extensive application of the composite layer to coat various implants, following items were examined; (1) surface chemistries of six implants, (2) mitogenic activities of FGF-2 in FGF-2-apatite composite layers on the implants, and (3) improved synthesis method of the composite layer for retention of the mitogenic activity of FGF-2., Hypothesis: The biological activity of FGF-2 in the composite layer is affected by the chemistries of the material and surface of implants., Materials and Methods: Six commercial products of pins and screws having different surface chemistries were coated with FGF-2-apatite composite layers. The composite layers were quantitatively analyzed for calcium (Ca), phosphorus (P) and FGF-2, and also evaluated the mitogenic activities of FGF-2. Improvement of the synthesis method was then attempted using two pin products., Results: Each commercial product had a chemically and morphologically characteristic surface. FGF-2-apatite composite layers were formed on all the commercial products. Although the Ca, P, and FGF-2 contents (4.7±0.9μg/mm, 2.2±0.4μg/mm, and 21.1±3.7ng/mm, respectively) and the Ca/P molar ratios (1.69±0.01) of the composite layers were almost the same, rate of retention of the mitogenic activity of FGF-2 in the composite layers significantly decreased on some pin products (3/12-4/12). The decrease in rate of retention of the mitogenic activity of FGF-2 was prevented by a two-step synthesis method to form a composite layer on a precoating with calcium phosphate (9/12-12/12)., Discussion: The chemistries of the implant surfaces had a significant impact on the retention of the mitogenic activity of FGF-2 in the composite layers formed on the implant. The two-step synthesis method was useful to retain mitogenic activity of FGF-2 regardless of the surface chemistries of the implants. The two-step synthesis method has potential to expand the applicability of FGF-2-apatite composite layers to a wider range of implants., Level of Evidence: III, Case control in vitro study., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Although cell transplantation has attracted much attention in regenerative medicine, animal models continue to be used in translational research to evaluate safety and efficacy because cell sources and transplantation modalities are so diverse. In the present study, we investigated the regenerative effects of human chondrocyte sheets on articular cartilage in a xenogeneic transplantation model using immune-deficient rats. Osteochondral defects were created in the knee joints of immune-deficient rats that were treated as Group A, untreated (without transplantation); Group B, transplantation of a layered chondrocyte sheet containing 5.0 × 10 5 cells (layered chondrocyte sheet transplantation); Group C, transplantation of a synoviocyte sheet containing 5.0 × 10 5 cells (synoviocyte sheet transplantation); or Group D, transplantation of both a synoviocyte sheet plus a layered chondrocyte sheet, each containing 5.0 × 10 5 cells (synoviocyte sheet plus layered chondrocyte sheet transplantation). Histological evaluation demonstrated that Group B showed cartilage regeneration with hyaline cartilage and fibrocartilage. In Groups C and D, the defect was filled with fibrous tissue but no hyaline cartilage. Transplanted cells were detected at 4 and 12 weeks after transplantation, but the number of cells had decreased at 12 weeks. Our results indicate that layered chondrocyte sheet transplantation contributes to articular cartilage regeneration; this model proved useful for evaluating these regenerative effects., (© 2020 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons Ltd.)

Strengthening the antitumor immune response to surpass the activation energy barrier associated with the immunosuppressive tumor microenvironment is an active area of cancer immunotherapy. Emerging evidence suggests that delivery of immunostimulatory molecules with the aid of a carrier system is essential for cancer immunotherapy. However, the size-dependent effect of the delivery system on immune-targeted sites and anticancer immune responses is yet to be comprehensively understood. Herein, to clarify the size-dependent effect of the delivery system on the underlying anticancer immune mechanism, rod-shaped hydroxyapatite (HA) particles with lengths from 100 nm to 10 μm are designed. HA rods stimulate anticancer immunity in a size-dependent manner. Shorter HA rods with lengths ranging from 100 to 500 nm promote antigen cellular uptake, dendritic cell (DC) maturation, and lymph node targeting antigen. In contrast, longer HA rods with lengths ranging from 500 nm to 10 μm prolong antigen retention and increase DC accumulation. Medium-sized HA rods with a length of 500 nm, taking advantage of both short and long rods, show optimized antigen release and uptake, increased DCs accumulation and maturation, highest CD4 + and CD8 + T cell population, and the best anticancer immunity in vivo . The present study provides a rod-scale design strategy for an immune-targeted delivery system toward cancer immunotherapy in the future.

Recombinant protein-based vaccines generally show limited immunogenicity and need adjuvants to achieve robust immune responses. Herein, to combine the excellent biocompatibility of hydroxyapatite (HA) and exciting adjuvant activity of silica, Si-doped HA nanorods with Si/P molar ratio from 0 to 0.65 were hydrothermally synthesized and evaluated as immunoadjuvants. Si-doping decreases the size and increases the BET surface area of the nanorods. Si-doping in HA nanorods increases the in vitro adjuvant activity, including CD11c + CD86 + expression and cytokine secretion of bone marrow derived dendritic cells (BMDCs). Moreover, Si-doping in HA increases the ex vivo adjuvant activity as shown by the increase in both Th1 and Th2 cytokines secretion. Si-doped HA nanorods are promising as a new immunoadjuvant., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Herein, mesoporous silica-zinc oxide (MS-Zn) micro-rosettes with controllable petal thickness were synthesized by a facile one-pot hydrothermal method. MS-Zn loaded with doxorubicin and polyinosinic-polycytidylic acid sodium salt not only significantly inhibits tumor growth but also effectively rejects tumor metastasis in vivo.

Background: Pin tract infection and loosening are major complications and challenges in the treatment of fractures by external fixation. To address this issue, we developed titanium pins coated with a fibroblast growth factor 2 (FGF-2)-apatite composite layer. The purpose of this initial clinical trial is to clarify the safety and feasibility of using these pins for the external fixation of distal radius fractures., Methods: Unstable, displaced fractures of the distal radius that were medically suitable for external fixation were treated using external fixation pins coated and uncoated with an FGF-2-apatite composite layer. The coated pin group (n = 5) comprised 5 women (average age, 70.4 ± 5.9 years), whereas the uncoated pin group (n = 10) comprised 8 women and 2 men (average age, 64.4 ± 11.7 years). The average duration of external fixation was 40.8 ± 1.3 and 41.6 ± 2.1 days for the coated and uncoated pin groups, respectively., Results: All patients achieved fracture union. One patient in the uncoated group had severe pin tract infection on the day of pin extraction. No pin loosening or difficulty in pin removal was observed in either group. Bacterial growth was present in 5% and 25% of the pin sites in the coated and uncoated groups, respectively ( p  = 0.059). No adverse events such as tumor formation were observed for more than 2 years after surgery in the coated pin group., Conclusions: This study clarified the safety and feasibility of using pins coated with an FGF-2-apatite composite layer for the external fixation of distal radius fractures.