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1.
J Dermatol ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32030784

RESUMO

Mucosal melanoma of the nasal cavity is a rare disease that has been consistently associated with poor outcome. While complete surgical excision offers the only prospect of a cure, it is associated with a high risk of surgical morbidity due to the challenging anatomical location, and most patients still develop incurable metastatic disease. The efficacy of immunotherapy on mucosal melanoma is lower in comparison with cutaneous melanoma, and mucosal melanoma rarely has BRAF mutations. Although preclinical data have shown that combination treatment with immune checkpoint inhibitors and radiotherapy (RT) improve the response, there have been few reports on the combination of RT and anti-programmed death 1 therapy for mucosal melanoma of the nasal cavity. We retrospectively investigated 10 cases of mucosal melanoma of the nasal cavity in which combined treatment was applied. The local control (LC) rate of the primary lesion and regional lymph nodes was favorably 100%. On the other hand, the median progression-free survival (PFS) time was 29.6 weeks (range, 2-82). The 6-month PFS rate was 60%. Although severe mucositis occurred in one patient, the incidence of treatment-related adverse events was not significantly increased. RT with anti-programmed death 1 antibody therapy for mucosal melanoma of the nasal cavity was tolerable and had the potential to improve LC and PFS.

2.
Br J Radiol ; : 20190625, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32031414

RESUMO

OBJECTIVE: Although various single genetic factors have been shown to affect radiosensitivity, high-throughput DNA sequencing analyses have revealed complex genomic landscapes in many cancer types. The aim of this study is to elucidate the association between accumulated alterations in driver and passenger genes and radiation therapy response. METHODS: We used 59 human solid cancer cell lines derived from 11 organ sites. Radiation-induced cell death was measured using a standard colony-forming assay delivered as a single dose ranging from 0 to 12 Gy. Comprehensive genomic data for the cell lines were acquired from the Catalogue Of Somatic Mutations In Cancer v. 80. Random forest classifiers were constructed to predict radioresistant phenotypes using genomic features. The Cancer Genome Atlas data sets were used to evaluate the clinical impact of the genomic feature following radiotherapy. RESULTS: The 59 cancer cell lines harbored either nucleotide variations or copy number variations in a median of 157 genes per cell. Radiosensitivity of the cancer cells was correlated with neither the number of driver gene mutations nor the number of passenger gene mutations. However, the proportion of driver gene alterations to total gene alterations in gene sets selected from the Kyoto Encyclopedia Genes and Genomes predicted radioresistant cells with sensitivity of 85% and specificity of 73%. High probability of radioresistance predicted by the model was associated with worse overall survival following definitive radiotherapy in patients of The Cancer Genome Atlas data sets. CONCLUSION: Cellular radiosensitivity was associated with the proportion of driver to total gene alterations in the selected oncogenic pathways, which may be a biomarker candidate for response to radiation therapy. ADVANCES IN KNOWLEDGE: These findings suggest that accumulated alterations in not only driver genes but also passenger genes affect radiosensitivity.

3.
Exp Anim ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32051389

RESUMO

Transgene insertion patterns are critical for the analysis of transgenic animals because the influence of transgenes may change depending on the insertion pattern (such as copy numbers and orientations of concatenations) and the insertion position in the genome. We previously reported a genomic walking strategy to locate transgenes in the genomes of transgenic mice (Exp Anim 53:103-111, 2004) and to analyze transgene insertion patterns (Exp Anim 55: 65-69, 2006). With such strategies, however, we could not determine the copy number of transgenes or global genome modification induced by transgene insertion due to read-length limitation. In this study, we used a long-read sequencer (MinION, Oxford Nanopore Technologies) to overcome this limitation. We obtained 922,210 reads using MinION with genomic DNA from a transgenic mouse strain (4C30, Proc Jpn Acad Ser B Phys Biol Sci 87: 550-562, 2011). Among the reads, we found one 21,457-bp read containing the transgene using a local BLAST search. Nucleotide dot plot analysis revealed that the transgene was inserted in the genome as a tandem concatemer with an almost entire construct (15-3,508 of 3,508 bp) and a partial fragment (4-660, 657 bp). Ensembl's BLAST search against the C57BL/6N genome revealed a 9,388-bp deletion at the insertion position in the intron of the Sgcd gene, confirming that mutations such as a large genomic deletion could occur at the time of transgene insertion. Thus, long-read sequencers are useful tools for the analysis of transgene insertion patterns.

4.
Anticancer Res ; 40(1): 393-399, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892592

RESUMO

AIM: This study was performed to confirm the superior overall survival (OS) after pulmonary oligo-recurrence compared to pulmonary sync-oligometastases in a large nationwide study. PATIENTS AND METHODS: Patients that met the following criteria were included: 1 to 5 lung-only metastases at the beginning of stereotactic body radiation therapy (SBRT) was performed between January 2004 and June 2015, and the biological effective dose (BED) of SBRT was 75 Gy or more. The parameters included in the analyses were age, gender, ECOG PS, primary lesion, pathology, oligoetastatic state, SBRT date, chemotherapy before SBRT, chemotherapy concurrent SBRT, chemotherapy after SBRT, maximum tumor diameter, number of metastases, field coplanarity, dose prescription, BED10, OTT of SBRT. RESULTS: In total, 1,378 patients with 1,547 tumors were enrolled. Oligo-recurrence occurred in 1,016 patients, sync-oligometastases in 118, and unclassified oligometastases in 121. The three-year OS was 64.0% for oligo-recurrence and 47.5% for sync-oligometastasis (p<0.001). In the multivariate analysis, the hazard ratio (HR) for sync-oligometastases versus oligo-recurrence was 1.601 (p=0.014). Adverse events of Grade 5 were occurred in 3 patients. CONCLUSION: This is the first nationwide to indicate that the OS of patients with pulmonary oligo-recurrence is better than that of patients with sync-oligometastases.


Assuntos
Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Radiocirurgia , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Adulto Jovem
5.
J Radiat Res ; 61(1): 92-103, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31822894

RESUMO

The aim of this work is to generate synthetic computed tomography (sCT) images from multi-sequence magnetic resonance (MR) images using an adversarial network and to assess the feasibility of sCT-based treatment planning for brain radiotherapy. Datasets for 15 patients with glioblastoma were selected and 580 pairs of CT and MR images were used. T1-weighted, T2-weighted and fluid-attenuated inversion recovery MR sequences were combined to create a three-channel image as input data. A conditional generative adversarial network (cGAN) was trained using image patches. The image quality was evaluated using voxel-wise mean absolute errors (MAEs) of the CT number. For the dosimetric evaluation, 3D conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT) plans were generated using the original CT set and recalculated using the sCT images. The isocenter dose and dose-volume parameters were compared for 3D-CRT and VMAT plans, respectively. The equivalent path length was also compared. The mean MAEs for the whole body, soft tissue and bone region were 108.1 ± 24.0, 38.9 ± 10.7 and 366.2 ± 62.0 hounsfield unit, respectively. The dosimetric evaluation revealed no significant difference in the isocenter dose for 3D-CRT plans. The differences in the dose received by 2% of the volume (D2%), D50% and D98% relative to the prescribed dose were <1.0%. The overall equivalent path length was shorter than that for real CT by 0.6 ± 1.9 mm. A treatment planning study using generated sCT detected only small, clinically negligible differences. These findings demonstrated the feasibility of generating sCT images for MR-only radiotherapy from multi-sequence MR images using cGAN.

6.
BMC Cardiovasc Disord ; 19(1): 298, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847799

RESUMO

BACKGROUND: Patients with some mutations in the lamin A/C (LMNA) gene are characterized by the presence of dilated cardiomyopathy (DCM), conduction abnormalities, ventricular tachyarrhythmias (VT), and sudden cardiac death (SCD). Various clinical features have been observed among patients who have the same LMNA mutation. Here, we show a family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, and a family history of conduction disorder, DCM, VT, and SCD. CASE PRESENTATION: A proband (female) with atrial fibrillation and bradycardia was implanted with a pacemaker in her fifties. Twenty years later, she experienced a loss of consciousness due to polymorphic VT. She had a serious family history; her mother and elder sister died suddenly in their fifties and sixties, respectively, and her nephew and son were diagnosed as having DCM. Genetic screening of the proband, her son, and nephew identified a nonsense mutation (c.475G > T, p.E159*) in the LMNA gene. Although the proband's left ventricular ejection fraction remained relatively preserved, her son and nephew's left ventricular ejection fraction were reduced, resulting in cardiac resynchronization therapy by implantation of a defibrillator. CONCLUSIONS: In this family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, DCM, SCD, and malignant VT occurred. Clinical manifestation of various atrial and ventricular arrhythmias and heart failure with reduced ejection fraction occurred in an age-dependent manner in all family members who had the nonsense mutation. It appears highly likely that the E159* LMNA mutation is related to various cardiac problems in the family of the current report.

7.
J Anus Rectum Colon ; 3(4): 167-174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31768467

RESUMO

OBJECTIVES: Left colic artery preserving lymph node dissection around the inferior mesenteric artery (IMA) is a standard procedure for rectal cancer surgery. Although the IMA sheath is a well-known structure, to our knowledge, there are no reports describing its microanatomy from an oncological point of view; therefore, there is no consensus on how to handle the sheath for accurate lymph node dissection around IMA. We aimed to investigate the components of the IMA sheath pathologically, focusing particularly on the presence of lymph nodes (LNs) and lymphatic ducts (LDs). METHODS: We evaluated rectal and sigmoid cancer specimens resected with high-tie technique in our institute in April 2017-April 2018. The specimens were collected consecutively, without any selection. In the resected specimens, the entire anatomical structure of IMA was investigated. We defined the IMA sheath as the tissues located between the surface of the IMA adventitia and collagenous layers connecting the outermost nerve fibers. The microanatomy around the IMA was examined using H&E staining, and LDs were identified using D2-40 immunohistochemistry. RESULTS: Twenty patients were enrolled. No LNs were observed within the sheath in any of the cases. However, there were a significant number of LDs (11.08 ± 3.35) within the sheath. CONCLUSIONS: Our anatomical definition of IMA sheath was feasible and objectively possible. These microanatomical results partially support the surgical concept of left colic artery preserving lymph node dissection around the IMA. It may be difficult to remove all lymphatic ducts without removing the IMA itself.

8.
Dent Mater J ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666486

RESUMO

Many ß-Ti alloys have been developed for, and used in, medical devices because of the corrosion resistance, biocompatibility, and exceptionally low Young's modulus. The aim of the present study was to investigate the histomorphometric aspects of peri-implant bone around Ti-Nb-Sn alloy implants and compare them with those in the case of commercially pure Ti (Ti). Fluorescent morphological observations of ST-2 cells on the substrate were performed and bone morphogenesis around implants in rat femur was evaluated. There was no difference between the cell morphology on Ti and those on the Ti-Nb-Sn alloy during observation for 24 h. A comparison of the Ti-Nb-Sn alloy implant and the Ti implant showed no significant differences between the bone-to-implant contact ratios or the bone fractions. These results suggest that the biological adaptations with Ti-Nb-Sn implants during a healing period are similar to those with Ti. Ti-Nb-Sn is therefore suitable for use in dental implants.

9.
J Appl Clin Med Phys ; 20(10): 74-83, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31502408

RESUMO

PURPOSE: We developed a technique to calculate the offset between room lasers and the radiation isocenter using a digital Winston-Lutz (WL) test with a starshot technique. We have performed isocenter localization quality assurance (QA) with submillimeter accuracy for a long period. Here we evaluated the feasibility and accuracy of this virtual starshot (VS) analysis for isocenter localization QA. METHODS: A 6-MV photon beam with a square multileaf collimator field was used to irradiate a WL sphere positioned at the intersection of the room lasers. Images were acquired using an electronic portal imaging device. A four-field WL test was performed, and the path of each beam was calculated from the offset between the beam and sphere. Virtual starshot analysis was used to analyze the radiation isocenter, which calculates the center of the beam paths by using a least-squares method, similar to the starshot analysis. Then, eight coplanar and 12 noncoplanar beams were irradiated to evaluate isocenter localization accuracy. RESULTS: Several VS analyses, using different WL spheres, were performed at three institutions, and the calculated accuracies were within 0.1 mm at all institutions. Long-term analysis showed that the isocenter localization accuracy was appropriately managed with three-dimensional accuracy within ± 0.5 mm for 90 months after the first laser adjustments. The offset between each beam and the room laser was within 0.6 mm and within 1.0 mm for eight coplanar and 12 noncoplanar beams, respectively, for 90 months. Cone-beam computed tomography images, acquired after verification beams, showed that the offset between the radiation isocenter and the imaging center was within 0.66 mm for 90 months. The isocenter localization accuracy within 1 mm was kept for long period at other four institutions. CONCLUSIONS: Long-term analysis showed the feasibility of VS analysis for isocenter localization QA, including room laser re-alignment, noncoplanar irradiation verification, and image guidance accuracy.

10.
Autoimmunity ; 52(5-6): 208-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31476889

RESUMO

Lupus nephritis (LN) is the secondary glomerulonephritis (GN) involved in systemic lupus erythematosus (SLE) and a typical immune complex-type GN. Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by systemic vasculitis and pauci-immune-type crescentic glomerulonephritis (CrGN) with ANCA production. Human AAV causes death due to lung haemorrhage and end-stage renal disease, for which renal replacement therapies are necessary. The SLE/AAV overlap syndrome was recently reported in humans. The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse is a unique model of human AAV showing production of myeloperoxidase (MPO)-ANCA. We previously discovered seven disease susceptibility quantitative trait loci (QTL) derived from SCG/Kj mice by linkage analysis. To investigate the individual functions of each QTL, and to identify AAV susceptibility genes, we introduced them into a B6/lpr background to establish SCG/Kj interval congenic mice (SICM). B6/lpr.C1scg mice, a type of SICM, exhibited the production of autoantibodies, including MPO-ANCA. The GN in B6/lpr.C1scg mice was not pauci-immune type: deposition of immunoglobulins and complement components was observed in nephritic glomeruli, similar to that in LN. The incidence of GN in female B6/lpr.C1scg mice was 100%. Granulocyte infiltration was also observed in the glomerular tuft and crescents. B6/lpr.C1scg mice also displayed vasculitis in multiple organs, most frequently the lung and kidney. Vasculitis was characterized by the infiltration of mononuclear cells to vascular walls followed by granulocyte infiltration, resembling human lupus vasculitis. The incidence of lung vasculitis was over 90% in male and female B6/lpr.C1scg mice. Blood MPO-ANCA levels were significantly associated with histopathological disease phenotypes. MPO deposition was observed in nephritic glomeruli, and granulocytes infiltrated into inflamed vessels and glomeruli. These observations suggest that the activation of granulocytes and local MPO release contribute to the pathogenesis of GN and vasculitis. As a monocongenic mouse, B6/lpr.C1scg mice show the association between murine chromosome 1 segment and autoimmunity. This strain can be used as a model of the SLE/AAV overlap syndrome, and will be useful for elucidating the mechanism of ANCA generation and the pathogenesis of CrGN and vasculitis, as well as in the search for genetic factors related to AAV.

11.
Technol Cancer Res Treat ; 18: 1533033819871327, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31455166

RESUMO

PURPOSE: Information on the short- and long-term outcomes of induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer is limited. We analyzed the short- and long-term outcomes of induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer. METHODS: Patients with non-small cell lung cancer who underwent induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer were retrospectively reviewed (initial treatment group, n = 31). Their results were compared to those patients who underwent surgery as an initial treatment during the same period (initial surgery group, n = 35). RESULTS: Downstaging was achieved in 14 (45%) patients in the initial treatment group. R0 resection was achieved in 28 (90%) patients in the initial treatment group and 31 (88%) patients in the initial surgery group. The 90-day mortality rate was 3% in each group. Postoperative complications occurred in 16 (52%) patients in the initial treatment group and 13 (37%) patients in the initial surgery group. The 5-year overall survival rate of the initial treatment group was significantly higher than that of the initial surgery group (62.6% vs 43.5%, P = .04). The 5-year overall survival rates of the initial treatment N0-1 group and the initial surgery N0-1 group were 88.9% and 49.3%, respectively; the difference was statistically significant (P = .02). Multivariate analysis using 4 factors (age [≤65 vs >65], cN [cN0-1 vs cN2], general condition [chemoradiotherapy fit vs chemoradiotherapy unfit], and treatment mode [induction chemoradiotherapy followed by surgery vs surgery as an initial treatment]) revealed that treatment mode (induction chemoradiotherapy followed by surgery) and cN status (cN0-1) were significantly associated with good overall survival and disease-free survival. CONCLUSIONS: Induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer could be performed with an acceptable degree of surgical risk. At present, it is thought to be one of the reasonable treatment approaches for selected patients with cT3-4 disease, even those with a cN0-1 status.

12.
J Oral Biosci ; 61(3): 149-156, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400543

RESUMO

BACKGROUND: Bone, dentin, and enamel are tissues formed through calcification, a process involving deposition of calcium phosphate minerals on extracellular organic matrices. Calcification, the underlying mechanism of which is unknown, is initiated with mineral deposition followed by advancing of the deposit and subsequent maturation of the mineral crystal. HIGHLIGHT: We have reviewed the current knowledge of how calcification proceeds during bone development, bone healing, and enamel and dentin development, based on reported studies. Previous studies reported by us and by other authors have suggested that degradation of some extracellular matrix (ECM) proteins is involved in calcification during bone and dentin development and bone healing in a manner similar to that previously reported for enamel development. CONCLUSION: The ECM proteins may inhibit mineral deposition and calcification, similar to the role of amelogenin during enamel development. The candidates for the amelogenin equivalents in bone and dentin have not been identified. Further studies are required to elucidate the regulatory mechanisms of bone and dentin calcification in light of specific ECM proteins that prevent calcification and enzymes that degrade these ECM proteins.

13.
Pathol Int ; 69(8): 441-449, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317621

RESUMO

Research using mouse lymphoma cell lines has resulted in many reports of glycosylation being a key regulator for the distant metastasis of mouse lymphoma cells in animal models. In contrast, there are only a few reports of experiments examining human lymphoma cell metastasis. The glycosylation pattern in human lymphoma shows that loss of Phaseolus vulgaris leukoagglutinating lectin (L-PHA) reactive oligosaccharides, and sialylation of L-PHA reactive oligosaccharides, are closely associated with a worse prognosis for diffuse large B cell lymphoma (DLBCL) patients. Sialic acid is related to cell adhesion to the extracellular matrix and metastasis of HBL-8 Burkitt lymphoma cells in a severe combined immunodeficiency (SCID) mouse animal model. In HBL-8 clones, differential cell surface sialylation was due to different expression levels of UDP-GlcNAc 2-epimerase (GNE). Knockdown of beta-galactoside alpha-2,6-sialyltransferase (ST6Gal1) resulted in enhanced lymphoma cell adhesion to galectin-1 in anaplastic large cell lymphoma cell line, H-ALCL. A fluorinated sialic acid analogue was shown to be useful for inhibiting sialyltransferase and may provide a new glycoengineering strategy for desialylation, as well as inhibiting invasion and metastasis and inducing cell death in lymphoma cell lines. This paper discusses glycosylation and sialylation in human lymphoma, and several glycoengineering therapeutic strategies for lymphoma.

14.
Materials (Basel) ; 12(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340468

RESUMO

Octacalcium phosphate (OCP) has been shown to enhance new bone formation, coupled with its own biodegradation, through osteoblasts and osteoclast-like cell activities concomitant with de novo hydroxyapatite (HA) formation and serum protein accumulation on its surface. However, the nature of the chemical environment surrounding OCP and how it affects its metabolism and regulates protein accumulation is unknown. The present study examined how the degree of supersaturation (DS) affects the bovine serum albumin (BSA) adsorption onto OCP in 150 mM Tris-HCl buffer at 37 °C and pH 7.4, by changing the Ca2+ ion concentration. The amount of BSA adsorbed onto OCP increased as the DS increased. In addition, the amount of newly formed calcium phosphate, which could be OCP, was increased, not only by increases in DS, but also at lower equilibrium concentrations of BSA. The increased adsorption capacity of BSA was likely related to the formation of calcium phosphate on the adsorbed OCP. Together the results suggested that the formation of new calcium phosphate crystals is dependent on both the DS value and the adsorbate protein concentration, which may control serum protein accumulation on the OCP surface in vivo.

15.
Anticancer Res ; 39(6): 2935-2940, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177132

RESUMO

AIM: To evaluate the toxicity and efficacy of re-irradiation with salvage stereotactic radiotherapy (SRT) for recurrent glioma using CyberKnife. PATIENTS AND METHODS: This study retrospectively investigated 35 patients with 48 recurrent grade 2-4 gliomas who received SRT between 1998 and 2011. Six patients (17.1%) had grade 2 gliomas, nine (25.7%) had grade 3 gliomas, and 20 (57.1%) had glioblastomas; all initially underwent surgery and conventional radiotherapy. The median initial and subsequent radiotherapy doses were 60 and 26 Gy, respectively. RESULTS: After a median follow-up period of 9.0 months, the only toxicity of grade 2 or more was radiation-induced brain necrosis in four patients (11.4%). The median overall and progression-free survival periods following re-irradiation were 9.0 and 3.0 months, respectively. Univariate analysis revealed that performance status at salvage re-irradiation was a significant predictor of progression-free survival. CONCLUSION: Salvage re-irradiation using CyberKnife is feasible, with an acceptable toxicity profile, for patients with recurrent glioma.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Recidiva Local de Neoplasia/radioterapia , Radiocirurgia/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Doses de Radiação , Estudos Retrospectivos , Terapia de Salvação/efeitos adversos , Resultado do Tratamento , Adulto Jovem
16.
Med Phys ; 46(9): 3757-3766, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30943311

RESUMO

PURPOSE: The SynchronyTM Respiratory Tracking System (SRTS) component of the CyberKnife® Robotic Radiosurgery System (Accuray, Inc., Sunnyvale CA) enables real-time tracking of moving targets by modeling the correlation between the targets and external surrogate light-emitting diode (LED) markers placed on the patient's chest. Previous studies reported some cases with respiratory phase shifts between lung tumor and chest wall motions. In this study, the impacts of respiratory phase shifts on the motion-tracking accuracy of the SRTS were investigated. METHODS: A plastic scintillator was used to detect the position of the x-ray beams. The scintillation light was recorded using a camera in a dark room. A moving phantom moved a U-shaped frame on the scintillator with a 4th power of sinusoidal functions. Three metallic markers for motion tracking and four fluorescent tapes were attached to the frame. The fluorescent tapes were used to identify phantom position and respiratory phase for each video frame. The beam positions collected, when considered relative to the phantom motion, represent the degree of tracking error. Beam position was calculated by adding error value to phantom position. Motions with respiratory phase shifts between the target and an extra stage mimicking chest wall motion were also tested for LED markers. Log files of the SRTS were analyzed to evaluate correlation errors. RESULTS: When target and LED marker motions were synchronized with a respiratory cycle of 4 s, the maximum tracking errors for 90% and 95% of beam-on time were 1.0 mm and 1.2 mm, respectively. The frequency of tracking errors increased when LED marker motion phase preceded target motion. Tracking errors that corresponded to 90% beam-on time were within 2.4 mm for 5-15% of phase shifts. In contrast, the tracking errors were very large when the LED marker delayed to the target motions; the maximum errors of 90% beam-on time were 3.0, 3.8, and 7.5 mm for 5%, 10%, and 15% of phase shifts, respectively. The patterns of the tracking errors derived from the scintillation light were very similar to those of the correlation data of the SRTS derived from the log files, indicating that the tracking errors caused mainly due to the errors in modeling the correlation data. With long respiratory cycle of 6 s, the tracking errors were significantly decreased; the maximum tracking errors for 95% beam-on time were 1.6 mm and 2.2 mm for early and delayed LED motion. CONCLUSION: We have investigated the motion-tracking accuracy of the CyberKnife SRTS for cases with the respiratory phase shift between the target and the LED marker. The maximum tracking errors for 90% probability were within 2.4 mm when the target delays to the LED markers. When LED marker delays, however, very large tracking errors were observed. With a long respiratory cycle, the tracking errors were greatly improved to less than 2.2 mm. Coaching slow breathing will be useful for accurate motion tracking radiotherapy.


Assuntos
Movimento , Radiocirurgia/métodos , Respiração , Imagens de Fantasmas , Planejamento da Radioterapia Assistida por Computador
17.
Int J Mol Sci ; 20(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836606

RESUMO

Bone is a highly vascularized tissue with a unique and complex structure. Long bone consists of a peripheral cortical shell containing a network of channels for vascular penetration and an inner highly vascularized bone marrow space. Bioprinting is a powerful tool to enable rapid and precise spatial patterning of cells and biomaterials. Here we developed a two-step digital light processing technique to fabricate a bone-mimetic 3D hydrogel construct based on octacalcium phosphate (OCP), spheroids of human umbilical vein endothelial cells (HUVEC), and gelatin methacrylate (GelMA) hydrogels. The bone-mimetic 3D hydrogel construct was designed to consist of a peripheral OCP-containing GelMA ring to mimic the cortical shell, and a central GelMA ring containing HUVEC spheroids to mimic the bone marrow space. We further demonstrate that OCP, which is evenly embedded in the GelMA, stimulates the osteoblastic differentiation of mesenchymal stem cells. We refined the design of a spheroid culture device to facilitate the rapid formation of a large number of HUVEC spheroids, which were embedded into different concentrations of GelMA hydrogels. It is shown that the concentration of GelMA modulates the extent of formation of the capillary-like structures originating from the HUVEC spheroids. This cell-loaded hydrogel-based bone construct with a biomimetic dual ring structure can be potentially used for bone tissue engineering.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Hidrogéis/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Biomimética , Bioimpressão , Vasos Sanguíneos/crescimento & desenvolvimento , Osso e Ossos/irrigação sanguínea , Osso e Ossos/efeitos dos fármacos , Gelatina/química , Gelatina/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrogéis/química , Osteogênese/efeitos dos fármacos , Poli-Hidroxietil Metacrilato/química , Poli-Hidroxietil Metacrilato/farmacologia , Impressão Tridimensional
18.
Acta Biomater ; 88: 477-490, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844570

RESUMO

Three-dimensional (3-D) cell culture can better mimic physiological conditions in which cells interact with adjacent cells and the extracellular matrix than monolayer culture. We have developed a 3-D cell culture device, the Oxy chip, which can be used to generate and supply oxygen to cell spheroids to prevent hypoxia. Here, we used the Oxy chip to generate hybrid spheroids comprising calcium phosphate (CaP) particles (hydroxyapatite (HA), ß-tricalcium phosphate (ß-TCP) or octacalcium phosphate (OCP)) and mesenchymal stem cells (MSCs, C3H10T1/2 cells or D1 cells) that can be used to analyze cell differentiation mechanisms. We showed that the 3-D cell-cell and cell-material interactions and oxygenation offered by the Oxy chip promoted osteoblastic differentiation of MSCs. We also used histomorphometric analysis of hematoxylin and eosin staining, quality analyses by µCT and collagen orientation observation with picrosirius red staining in bone regeneration following implantation of three CaPs in a critical-sized defect in mouse calvaria. The in vivo bone formation capacity of the three tested CaP materials was OCP ≥ ß-TCP > HA: the newly formed bone by OCP had a structure relatively close to that of the calvaria intact bone. When MSCs were 3-D cultured with the CaP materials using the Oxy chip, the in vitro osteogenic capacity of these materials was highly similar to trends observed in vivo. The in vitro alkaline phosphatase activity of D1 cells had the highest correlation with in vivo bone volume (R = 0.900). Chemical and FTIR spectroscopic analyses confirmed that differentiation of D1 cells could be associated with amorphous calcium phosphate (ACP) precipitation concomitant with OCP hydrolysis. Taken together, hybrid spheroid cultures using the Oxy chip can be used to screen and predict bone forming potential of bone substitute materials. STATEMENT OF SIGNIFICANCE: An oxygen permeable-culture chip (Oxy chip) can be used to induce formation of cell spheroids by mesenchymal stem cells (MSCs). Use of the Oxy chip avoids hypoxia in the spheroid core and enhances MSC osteoblastic differentiation relative to conventional spheroid culture methods. The present study showed that the Oxy chip mimics the in vivo environment associated with bone formation and can be used to generate hybrid spheroids consisting of calcium phosphates and MSCs that are useful for analyzing cell differentiation mechanisms. Bone formation analysis following implantation of calcium phosphate materials in mouse calvaria defects showed positive correlation with the in vitro results. We propose that hybrid spheroids cultured on the Oxy chip can be used to screen and predict the bone forming potential of bone substitute materials.

19.
Drug Des Devel Ther ; 13: 555-568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30787596

RESUMO

Background: Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis is a pauci-immune disease with the inflammation of the small blood vessels. The efficacies of antibody drugs for induction therapies of vasculitis vary among cases. Here, we developed a novel clone of a single chain Fv region (ScFv) with vasculitis-specific therapeutic potential. Materials and methods: The clone, termed VasSF, was selected from our Escherichia coli expression library of recombinant human ScFv based on the therapeutic efficacy in an SCG/Kj mouse model of MPO-ANCA-associated vasculitis (MAAV), such as improvement of the urinary score and decreased crescent formation in glomeruli, granulomatous in lung, MPO-ANCA biomarkers, the anti-moesin antibody, and some cytokine levels. Results: We identified vasculitis-associated apolipoprotein A-II (VAP2) as a target molecule of the clone and confirmed the independently-established VAP2 antibodies were also therapeutic in SCG/Kj mice. In MAAV, MPO-ANCA and cytokines stimulate neutrophils by facilitating heterodimer formation of VAP2 with apolipoprotein A-I in HDL. Conclusion: VasSF would constitute a novel antibody drug for vasculitis by suppressing the heterodimer formation of the apolipoproteins.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos de Cadeia Única/uso terapêutico , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Biblioteca de Peptídeos , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/uso terapêutico , Anticorpos de Cadeia Única/química , Anticorpos de Cadeia Única/isolamento & purificação
20.
Acta Biomater ; 88: 514-526, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776505

RESUMO

Effect of octacalcium phosphate/gelatin composite (OCP/Gel) on angiogenesis was studied by its implantation in rat calvaria critical-sized defect in relation to bone regeneration for 2 and 4 weeks. The implantation of OCP/Gel disks was analyzed by radiomorphometry using a radiopaque material perfusion (Microfil®) method and histomorphometry by hematoxylin and eosin-staining before and after the decalcification. Effect of the OCP dose in the range up to 4 mg per well on the capillary-like tube formation by human umbilical vein endothelial cells (HUVECs) was also examined in a transwell cell culture. The results showed that the blood vessels formation by OCP/Gel group was significantly higher at 2 weeks than other groups but decreased at 4 weeks during the advancement of new bone formation. The capillary-like tube formation was highest in an OCP dose of 1 mg per well while other OCP doses above or below 1 mg did not show such a stimulatory effect. The results established both in vivo and in vitro confirmed that OCP has a positive effect on angiogenesis during bone regeneration in a suitable dose ranges, suggesting that the angiogenesis stimulated by OCP could be involved in the OCP/Gel-enhanced bone regeneration. STATEMENT OF SIGNIFICANCE: We have reported that octacalcium phosphate (OCP) materials display stimulatory capacities on the bone tissue-related cells. However, the effect of OCP on the angiogenesis and its relation to the OCP-enhanced bone regeneration is unknown. This study confirmed the capacity of OCP on angiogenesis before increasing the new bone mass after the implantation of a composite of OCP and gelatin (OCP/Gel). The blood vessels formation took place associated with the area beginning of the new bone formation, which finally decreased together with development of bone formation. Because OCP was ascertained stimulating the capillary-like tube formation in HUVEC culture with a certain OCP dose, the present study is the first report showing the capacity of OCP on angiogenesis during the OCP/Gel-enhanced bone regeneration.

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