Dynamic collision behavior between osteoblasts and tumor cells regulates the disordered arrangement of collagen fiber/apatite crystals in metastasized bone

Bone metastasis is one of the most intractable bone diseases; it is accompanied with a severe mechanical dysfunction of bone tissue. We recently discovered that the disorganized collagen/apatite microstructure in cancer-bearing bone is a dominant determinant of the disruption of bone mechanical function; disordered osteoblast arrangement was found to be one of the principal determinants of the deteriorated collagen/apatite microstructure. However, the precise molecular mechanisms regulating the disordered osteoblast arrangement triggered by cancer invasion are not yet understood. Herein, we demonstrate a significant disorganization of bone tissue anisotropy in metastasized bone in our novel ex vivo metastasis model. Further, we propose a novel mechanism underlying the disorganization of a metastasized bone matrix: A dynamic collision behavior between tumor cells and osteoblasts disturbs the osteoblast arrangement along the collagen substrate.Matsugaki A., Harada T., Kimura Y., et al. Dynamic collision behavior between osteoblasts and tumor cells regulates the disordered arrangement of collagen fiber/apatite crystals in metastasized bone. International Journal of Molecular Sciences, 19, 11, 3474. https://doi.org/10.3390/ijms19113474

Production of viral vectors using recombinase-mediated cassette exchange

DNA viruses are often used as vectors for foreign gene expression, but large DNA region from cloned or authentic viral genomes must usually be handled to generate viral vectors. Here, we present a unique system for generating adenoviral vectors by directly substituting a gene of interest in a small transfected plasmid with a replaced gene in a replicating viral genome in Cre-expressing 293 cells using the recombinase-mediated cassette exchange (RMCE) reaction. In combination with a positive selection of the viral cis-acting packaging signal connected with the gene of interest, the purpose vector was enriched to 97.5 and 99.8% after three and four cycles of infection, respectively. Our results also showed that the mutant loxP V (previously called loxP 2272), a variant target of Cre used in the RMCE reaction, was useful as a non-compatible mutant to wild-type loxP. This method could be useful for generating not only a large number of adenovirus vectors simultaneously, but also other DNA virus vectors including helper-dependent adenovirus vector

Impaired alignment of bone matrix microstructure associated with disorganized osteoblast arrangement in malignant melanoma metastasis

Malignant melanoma favors spreading to bone, resulting in a weakened bone with a high fracture risk. Here, we revealed the disorganized alignment of apatite crystals in the bone matrix associated with the homing of cancer cells by developing an artificially controlled ex vivo melanoma bone metastasis model. The ex vivo metastasis model reflects the progressive melanoma cell activation in vivo, resulting in decreased bone mineral density and expression of MMP1-positive cells. Moreover, less organized intercellular connections were observed in the neighboring osteoblasts in metastasized bone, indicating the abnormal and randomized organization of bone matrix secreted by disconnected osteoblasts. Our study revealed that the deteriorated microstructure associated with disorganized osteoblast arrangement was a determinant of malignant melanoma-related bone dysfunction.Matsugaki A., Kimura Y., Watanabe R., et al. Impaired alignment of bone matrix microstructure associated with disorganized osteoblast arrangement in malignant melanoma metastasis. Biomolecules, 11, 2, 1. https://doi.org/10.3390/biom11020131

Adenovirus-mediated transfection of caspase-8 sensitizes hepatocellular carcinoma to TRAIL- and chemotherapeutic agent-induced cell death

AbstractCaspase-8 belongs to the cysteine protease family and is known to be activated at the initial step in the cascade of TRAIL-induced apoptosis. The activation of procaspase-8 can be blocked by a relatively large amount of c-FLIP, which renders resistance to death receptor-mediated apoptosis in many types of cancer cells. To ask if extrinsic over-expression of caspase-8 contributes to the induction of apoptosis, we introduced the caspase-8 gene into HCC cells using an adenoviral (Adv) vector (Adv-Casp8). We demonstrated that Adv-Casp8 increased expression of active forms of caspase-8 in MOI-dependent manner. A large amount of Adv-Casp8 (MOI of 50) induced apoptosis significantly in HCC cells and resulted in downregulation of c-FLIP (in SK-Hep1, HLE, and HepG2 cells), XIAP, survivin, and Bcl-xL (in HLE cells) and dynamic release of cytochrome c and Smac from the mitochondria into the cytosol. On the other hand, a small amount of Adv-Casp8 (MOI of 10) causes a slight but detectable increase in the level of apoptosis with only a small effect on anti-apoptotic proteins and mitochondrial activation. However, small amounts of Adv-Casp8 augmented TRAIL- or chemotherapeutic agent-induced cell death (with an MOI of 10 or 20, respectively). These results suggest both that exogenous over-expression of caspase-8 by Adv-Casp8 may be essential for induction of HCC cell death and that the combination of Adv-Casp8 and TRAIL or chemotherapeutic agents could provide a useful strategy for treatment of HCC

Group cognitive behavior therapy for Japanese patients with social anxiety disorder: Preliminary outcomes and their predictors

© 2007 Chen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background A number of studies have provided strong evidence for the use of cognitive behavior therapy (CBT) in the treatment of social anxiety disorder (SAD). However, all of the previous reports were from Europe and North America and it is unknown whether Western psychological therapies are effective for SAD in non-Western cultures. The present pilot study aimed to evaluate CBT program for SAD which was originally developed for Western patients, among Japanese patients. Methods Fifty-seven outpatients who participated in group CBT for SAD were evaluated using eight self-reported and one clinician-administered questionnaires to measure various aspects of SAD symptomatology at the beginning and at the end of the program. Pre- and post-treatment scores were compared and the magnitude of treatment effect was quantified as well based once on the intention-to-treat (ITT) and once among the completers only. We also examined baseline predictors of the CBT outcomes. Results Seven patients (12%) did not complete the program. For the ITT sample, the percentage of reduction was 20% to 30% and the pre to post treatment effect sizes ranged from 0.37 to 1.01. Among the completers, the respective figures were 20% to 33% and 0.41 to 1.19. We found no significant pretreatment predictor of the outcomes. Conclusion Group CBT for SAD is acceptable and can bring about a similar degree of symptom reduction among Japanese patients with SAD as among Western patients

従軍慰安婦問題をめぐる言説の現在メディアはどう伝えたか

本論文は、映像メディアで伝えられる従軍慰安婦問題をめぐる言説が視聴者にどのように伝わるかについて、視聴調査のデータに基づき分析を行なったものである。戦後60年を経た現在においても、従軍慰安婦問題は様々な歴史認識が交錯する問題の一つであり、「従軍慰安婦」をめぐっては、いくつかの言説が存在している。本論文では、それらを整理した上で、2001年に「従軍慰安婦」問題を扱ったNHKの番組が、どのような言説の政治の下で改編され問題となったのかを明らかにするとともに、この番組は視聴者の「従軍慰安婦」問題の認識にどのような影響を与えたかについて、番組視聴調査の結果から考察を行なった

病院外来部のウェイファインディング・デザインに関する研究

Among the hospital departments, outpatient department should be the one where many patients could wander from the right path. The purpose of this study is to find out the guidelines for the planning of the safe and comfortable way-finding environment for the outpatient department. First, 190 Japanese hospitals built after 1985 with 300 or more beds were classified by the space components of the outpatient department from the way-finding design point of view. Next, comparative analysis was made on the information signs for the patients at 5 hospitals. These 5 hospitals had different kinds of space components. It was found that the visual acknowledgment by the patients heavily depends on the amount of information gathered from the space components as well as from the information signs. Therefore, by the good utilization of such space elements as light court and well space, we could reduce the stray patients even with less number of information signs

Effects of astigmatic defocus on binocular contrast sensitivity

MethodsEighteen normal volunteers (30.5 ± 6.0 [mean ± SD] years) were recruited. After correcting each refractive error by spectacles, against-the-rule (ATR) or with-the-rule (WTR) astigmatism of +1.00, +2.00 and +3.00 D was intentionally produced in both eyes, and then binocular CS was measured. The cylindrical addition of different powers (+1.00–+3.00 D) was compensated with spherical lenses so that the spherical equivalent refraction became zero in each eye. Subsequently, the above cylindrical addition was monocularly induced, and binocular CS was measured again. The relation between CS and astigmatic power, axis, and monocular or binocular astigmatism was investigated.ResultsWith binocular ATR and WTR astigmatism, increases in astigmatic power significantly correlated with decreases in the area under the log contrast sensitivity function (AULCSF). With monocular astigmatic defocus, astigmatic power addition did not affect AULCSF. With binocular astigmatic defocus of high-power (+2.00 and +3.00 D), ATR astigmatism deteriorated AULCSF more than WTR astigmatism. In a comparison between binocular and monocular astigmatic defocus, CS was significantly worse with binocular astigmatic defocus than with monocular astigmatic defocus at higher spatial frequencies regardless of astigmatic power.ConclusionsBinocular astigmatic defocus deteriorates CS depending on the amount of astigmatic power. ATR astigmatism reduces CS more than WTR astigmatism dose. In addition, binocular astigmatic defocus affects CS more severely than monocular astigmatic defocus especially at high spatial frequencies

B cell-derived GABA elicits IL-10⁺ macrophages to limit anti-tumour immunity

GABAを標的とする抗腫瘍免疫機構 --代謝産物を介した免疫細胞間制御の一端を解明--. 京都大学プレスリリース. 2021-11-10.Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8⁺ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses