iPS細胞とマイクロ流体気道チップ技術を組み合わせた多細胞での繊毛病モデルの構築

京都大学新制・課程博士博士(医学)甲第23571号医博第4785号新制||医||1054(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 齊藤 博英, 教授 大森 孝一, 教授 大鶴 繁学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Insulin receptor substrate-1 (IRS-1) forms a ribonucleoprotein complex associated with polysomes

AbstractInsulin receptor substrates (IRSs) are known to play important roles in mediating intracellular insulin-like growth factors (IGFs)/insulin signaling. In this study, we identified components of messenger ribonucleoprotein (mRNP) as IRS-1-associated proteins. IRS-1 complex formation analysis revealed that IRS-1 is incorporated into the complexes of molecular mass more than 1000kDa, which were disrupted by treatment with RNase. Furthermore, oligo(dT) beads precipitated IRS-1 from cell lysates, showing that the IRS-1 complexes contained messenger RNA. Taken together with the data that IRS-1 was fractionated into the polysome-containing high-density fractions, we concluded that IRS-1 forms the novel complexes with mRNPs

Core-shell hydrogel microfiber-expanded pluripotent stem cell-derived lung progenitors applicable to lung reconstruction in vivo

ヒトiPS細胞由来肺前駆細胞の拡大培養とマウス肺への移植・生着に成功 --肺再生医療の実現へ大きな一歩--. 京都大学プレスリリース. 2021-07-30.Lung transplantation is the only treatment available for end-stage lung diseases; however, donor shortage is a global issue. The use of human pluripotent stem cells (hPSCs) for organ regeneration is a promising approach. Nevertheless, methods for the expansion of isolated hPSC-derived lung progenitors (hLPs) for transplantation purposes have not yet been reported. Herein, we established an expansion system of hLPs based on their three-dimensional culture in core-shell hydrogel microfibers, that ensures the maintenance of their bipotency for differentiation into alveolar and airway epithelial cells including alveolar type II (AT2) cells. Further, we developed an efficient in vivo transplantation method using an endoscope-assisted transtracheal administration system; the successful engraftment and in vivo differentiation of hLPs into alveolar epithelial cells (incorporated into the alveoli) was observed. Importantly, expanded hLPs in the context of microfibers were successfully transplanted into the murine lungs, opening avenues for cell-based therapies of lung diseases. Therefore, our novel method has potential regenerative medicine applications; additionally, the high-quality hLPs and AT2 cells generated via the microfiber-based technology are valuable for drug discovery purposes

Adaptive Fighting Game Computer Player by Switching Multiple Rule-based Controllers

This paper proposes the design of a computer player for fighting games that has the advantages of both rule-based and online machine learning players. This method combines multiple computer players as game controllers and switches them at regular time intervals. In this way the computer player as a whole tries to act advantageously against the current opponent player. To select appropriate controllers against the opponent out of the multiple controllers, we use the Sliding Window Upper Confidence Bound (SW-UCB) algorithm that is designed for non-stationary multi-armed bandit problems. We use the FightingICE platform as a testbed for our proposed method. Some experiments show the effectiveness of our proposed method in fighting games. The computer player consists of 3 rule-based computer players, and our method outperforms each of the 3 players. Additionally the proposed method improves the performance a little bit against an online machine learning player

Neuronal Intranuclear Inclusion Disease Presenting with Resting Tremor

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with various neurological symptoms. A 73-year-old woman presented with slowly progressive tremor in both hands. The resting tremor was enhanced by cognitive activity and walking. However, there were no other signs of parkinsonism. Levodopa and trihexyphenidyl were ineffective against the tremor. A diagnosis of NIID was made based on skin biopsy findings. The tremor in this case was very similar to that seen in Parkinson's disease (PD). Previous reports and the present case indicate that NIID patients can develop tremor that is similar in character to that seen in PD. NIID should be considered in the differential diagnosis of resting tremor similar to PD

In Vitro Disease Modeling of Hermansky-Pudlak Syndrome Type 2 Using Human Induced Pluripotent Stem Cell-Derived Alveolar Organoids

iPS細胞を用いて遺伝性間質性肺炎の病態解析に成功 --間質性肺炎の原因究明の足がかりに--. 京都大学プレスリリース. 2019-02-19.It has been challenging to generate in vitro models of alveolar lung diseases, as the stable culture of alveolar type 2 (AT2) cells has been difficult. Methods of generating and expanding AT2 cells derived from induced pluripotent stem cells (iPSCs) have been established and are expected to be applicable to disease modeling. Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by dysfunction of lysosome-related organelles, such as lamellar bodies (LBs), in AT2 cells. From an HPS type 2 (HPS2) patient, we established disease-specific iPSCs (HPS2-iPSCs) and their gene-corrected counterparts. By live cell imaging, the LB dynamics were visualized and altered distribution, enlargement, and impaired secretion of LBs were demonstrated in HPS2-iPSC-derived AT2 cells. These findings provide insight into the AT2 dysfunction in HPS patients and support the potential use of human iPSC-derived AT2 cells for future research on alveolar lung diseases

Serum albumin level as a potential marker for deciding chemotherapy or best supportive care in elderly, advanced non-small cell lung cancer patients with poor performance status

Abstract Background There have been few data on the chemotherapy in elderly advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS), and usefulness of chemotherapy for such patients remains unclear. The objective of this study was to identify factors that predicted the survival benefit of chemotherapy. Methods All consecutive elderly patients (≥75 years) with advanced NSCLC, Eastern Cooperative Oncology Group PS ≥2, EGFR mutation wild type/unknown, and newly diagnosed from January 2009 to December 2012 at a tertiary hospital were retrospectively reviewed. Results We enrolled 59 patients, and 31 patients received at least one chemotherapy regimen (chemotherapy group). However, 28 patients received best supportive care (BSC) alone (BSC group). The proportion of PS 2 and serum albumin levels was significantly higher in the chemotherapy group than in the BSC group. In the chemotherapy group, log-rank testing did not show statistically significant differences in overall survival (OS) between the single-agent therapy group and carboplatin-based doublet therapy group; however, the OS of patients receiving chemotherapy for only 1 cycle (early termination) was significantly shorter than patients receiving chemotherapy for ≥2 cycles. Hypoalbuminemia was not only a risk factor for the early termination of chemotherapy but also an independent prognostic factor in the chemotherapy group. A receiver operating characteristic curve analysis showed that the best cut-off value was 3.40 g/dL. In patients with serum albumin levels ≥3.40 g/dL, OS was significantly better in the chemotherapy group than in the BSC group (p = 0.0156), however, patients with serum albumin levels <3.40 g/dL exhibited poor prognosis regardless of the presence or absence of chemotherapy. Conclusion In the elderly NSCLC patients with poor PS, serum albumin levels may help identify certain patient populations more likely to receive a survival benefit of systemic chemotherapy