セルローストリプロピオネートのコンフォーメーション解析

セルローストリプロピオネート (CTP) の1本の分子鎖について, 1残基内および連続する残基間の非結合原子間反発エネルギーを考慮したパーチュアルボンド法により, コンフォーメーション解析を行なった。X線繊維図から, CTPの繊維周期は1. 508nmと計算され, 消滅則より分子鎖方向に3回らせん軸が存在する。このように分子軸方向に3回らせん軸をもつセルローストリプロピオネートの構造は, 他のセルローストリエステル同族体 (セルローストリアセテート, セルローストリブチレート, セルローストリバレレート) が2回らせん構造を有するのに対して, 特異的である。エネルギ一計算および非結合原子間の容認されることのできない接触の有無を調べた結果, 右巻き3_1らせんに比べ, 左巻き3_2らせんの方が低いコンフォーメーションエネルギーを持つ事がわかった。考慮した16のモデルのうち, 最も可能性の高い左巻き3_2らせんのコンフォーメーションにおいては, 側鎖はらせん軸に対しほぼ垂直に伸びた構造を持つ。The conformation of single cellulose tripropionate chain was studied by the virtual bond method considering nonbonded repulsive energy within the residue and between the contiguous residues. From X-ray data, the fiber repeat distance was found to be 1.508nm with systematic absences of threefold screw axis along the molecule. This threefold helical symmetry of cellulose tripropionate is unique among cellulose triester homologues in which the twofold screw axis is predominant. Considering 16 most probable conformations, 8 in right-handed and 8 in left-handed helical conformations, a left-handed 32 helical conformation was most favorable based on conformation analysis and short contact examinations between any pair of nonbonded atoms. The propionyl side chains are considerably extended almost perpendicularly to the helix axis

In vivo local transcranial static magnetic field stimulation alters motor behavior in normal rats

Transcranial static magnetic field stimulation (tSMS) has inhibitory neuromodulatory effects on the human brain. Most of the studies on static magnetic fields have been performed in vitro. To further understand the biological mechanisms of tSMS, we investigated the effects of in vivo tSMS on motor behavior in normal awake rats. The skull of a male Wistar rat was exposed and a polyethylene tube was attached to the skull using dental cement at the center of the motor cortex (n = 7) or the other cortex (n = 6). By attaching a cylindrical NdFeB neodymium magnet into the tube, in vivo tSMS (REAL) was performed. For SHAM, we applied a similar size non-magnetic stainless-steel cylinder. All rats received twice each SHAM and REAL stimulation crossover design, and motor function was measured during the stimulation. Activity level and asymmetry of forelimb use were not affected, but less accurate movements in the horizontal ladder test were found in REAL stimulation of the motor cortex. This study shows that in vivo tSMS has inhibitory neuromodulatory effects on motor behavior depending on the stimulated region on the rat cortex

<Preliminary>Change of X-ray Diffraction Peaks in Aliphatic Cellulose Ester Homologues

この論文は国立情報学研究所の学術雑誌公開支援事業により電子化されました。While characterizing aliphatic cellulose ester homologues using various instruments we have noticed that their first (the largest) X-ray diffraction peak always moved toward smaller angle (larger spacing) as the number of carbon in the acyl group was increased. This phenomenon might give us an insight of the molecular structure of the cellulose ester homologues, and it is reported as a preliminary

The clinical benefits of immune checkpoint inhibitor for thymic carcinomas ∼experience of single public hospital in Japan∼

Thymic carcinomas is rare and highly aggressive carcinoma. Most patients with them are diagnosed as being at surgically unresectable stages due to it. There are several reports which showed the effect of chemotherapy, however, it is controversial. Recently, immune checkpoint inhibitors have changed conventional chemotherapy due to their effect against various types of cancers. We administered nivolumab, anti-Programmed Cell Death (PD)-1 antibody, to four patients with unresectable thymic carcinomas who had previously undergone conventional chemotherapy. A histopathology on tumors from these patients revealed the presence of squamous cell carcinoma and PD-L1 high expression. After treatment with nivolumab, it seemed to be beneficial to all patients; The best clinical responses of 3 patients were partial response and that of the other one was stable disease. None of them experienced severe immune-related adverse events. Our results suggest the potential benefits of using these inhibitors to treat thymic carcinomas in real world clinical setting as is the cases in recent clinical trials for the evaluation of immune checkpoint inhibitors for the treatment of thymic carcinoma

Enhanced antitumor efficacy of fiber‐modified, midkine promoter‐regulated oncolytic adenovirus in human malignant mesothelioma

Oncolytic virotherapy using adenoviruses has potential for therapeutic benefits in malignant mesothelioma. However, the downregulation of coxsackie virus/adenovirus receptor (CAR) expression is frequently a critical rate-limiting factor that impedes the effectiveness of adenovirus serotype 5 (Ad5)-based vectors in many cancer types. We evaluated CAR (Ad5 receptor) and CD46 (adenovirus serotype 35 [Ad35] receptor) expression in six human malignant mesothelioma cell lines. Very low CAR expression was observed in MSTO-211H and NCI-H2052 cells, whereas the other cell lines showed strong expression. In contrast, CD46 was highly expressed in all mesothelioma cell lines. On this basis, we replaced the CAR binding sequence of Ad5 with the CD46 binding sequence of Ad35 in the replication-defective adenoviruses and the tumor-specific midkine promoter-regulated oncolytic adenoviruses. By this fiber modification, the infectivity, virus progeny production, and in vitro cytocidal effects of the adenoviruses were significantly enhanced in low CAR-expressing MSTO-211H and NCI-H2052 cells, also resulting in similar or even higher levels in high CAR-expressing mesothelioma cell lines. In MSTO-211H xenograft models, the fiber-modified oncolytic adenovirus significantly enhanced antitumor effect compared to its equivalent Ad5-based vector. Our data demonstrate that Ad35 fiber modification of binding tropism in a midkine promoter-regulated oncolytic Ad5 vector confers transductional targeting to oncolytic adenoviruses, thereby facilitating more effective treatment of malignant mesothelioma

Enhanced antitumor efficacy of fiber-modified, midkine promoter-regulated oncolytic adenovirus in human malignant mesothelioma

Oncolytic virotherapy using adenoviruses has potential for therapeutic benefits in malignant mesothelioma. However, the downregulation of coxsackie virus/adenovirus receptor (CAR) expression is frequently a critical rate-limiting factor that impedes the effectiveness of adenovirus serotype 5 (Ad5)-based vectors in many cancer types. We evaluated CAR (Ad5 receptor) and CD46 (adenovirus serotype 35 [Ad35] receptor) expression in six human malignant mesothelioma cell lines. Very low CAR expression was observed in MSTO-211H and NCI-H2052 cells, whereas the other cell lines showed strong expression. In contrast, CD46 was highly expressed in all mesothelioma cell lines. On this basis, we replaced the CAR binding sequence of Ad5 with the CD46 binding sequence of Ad35 in the replication-defective adenoviruses and the tumor-specific midkine promoter-regulated oncolytic adenoviruses. By this fiber modification, the infectivity, virus progeny production, and in vitro cytocidal effects of the adenoviruses were significantly enhanced in low CAR-expressing MSTO-211H and NCI-H2052 cells, also resulting in similar or even higher levels in high CAR-expressing mesothelioma cell lines. In MSTO-211H xenograft models, the fiber-modified oncolytic adenovirus significantly enhanced antitumor effect compared to its equivalent Ad5-based vector. Our data demonstrate that Ad35 fiber modification of binding tropism in a midkine promoter-regulated oncolytic Ad5 vector confers transductional targeting to oncolytic adenoviruses, thereby facilitating more effective treatment of malignant mesothelioma

Serial interferon-gamma release assay in lung cancer patients receiving immune checkpoint inhibitors: a prospective cohort study

Recent advancements in cancer immunotherapy using immune checkpoint inhibitors (ICIs) have received considerable attention. Although advantageous, ICI therapies cause unique immune-related adverse events (irAEs) in some patients. Moreover, infectious diseases, such as tuberculosis, have been recognized as emerging concerns during immunotherapy. We aimed to evaluate the interferon-gamma release assay (IGRA) conversion rate and active tuberculosis incidence during immunotherapy to elucidate the incidence of tuberculosis reactivation after ICI therapy induction. We prospectively assessed IGRA results in lung cancer patients who received ICI monotherapy before ICI treatment and at 6 and 12 months after ICI treatment. We also assessed computed tomography findings to determine the presence of active tuberculosis when positive IGRA results were obtained. The ICIs used were nivolumab, pembrolizumab, atezolizumab, and durvalumab. In all, 178 patients were prospectively recruited between March 2017 and March 2020. Of these, 123 completed serial IGRAs, of whom 18, 101, and 4, respectively, had positive, negative, and indeterminate IGRAs at baseline. Three and four patients, respectively, showed IGRA reversion and conversion during immunotherapy. One patient with a sustained, stable positive IGRA and one with IGRA conversion developed active pulmonary tuberculosis during immunotherapy. We found that 3.3% and 1.6% of the patients developed IGRA conversion and active tuberculosis, respectively. Of the four patients who developed IGRA conversion, one developed active pulmonary tuberculosis during immunotherapy. Another patient with sustained, stable positive IGRA developed active tuberculosis. Physicians should be alert to tuberculosis development during ICI therapy, and IGRA testing is a useful tool to assess the risk of developing active tuberculosis.</p

Continuous behavioral observation reveals the function of drifting seaweeds for Seriola spp. juveniles

ABSTRACT: A large number of fish species are associated with drifting seaweeds; however, the ecological significance of such seaweeds for fishes remains unclear. Here, we developed a raft equipped with a seaweed clump, interval still/video cameras, and a GPS satellite buoy. This novel monitoring system was used to monitor the schooling and associative behavior of Seriola spp. juveniles with seaweed for up to 1 wk in the East China Sea. We observed diel behavioral patterns of the fish, which swam around the seaweeds during the day and remained ‘attached’ to the seaweed or to conspecifics at night. This nighttime behavioral pattern suggests that the fish may use drifting seaweed to maintain schools at night when vision is less effective. Solitary individuals and those in smaller schools tended to remain close to the seaweed, whereas fish in larger schools were observed swimming actively around the seaweed. Additionally, some of the solitary fish and small schools escaped into the seaweed when potential predators appeared. As the school size of the fish increased over time, solitary individuals and small schools may have used drifting seaweeds as a shelter from predators until the fish could gather to form larger schools. We suggest that drifting seaweeds have multiple ecological functions for Seriola spp. and other seaweed-associated fishes, and the knowledge of these functions will be useful in designing conservation and management measures for the associated fishes