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イマチニブ耐性または不耐の消化管間質腫瘍に対するスニチニブ治療における標準投与法と減量投与法の安全性と有効性の比較
Get PDF新潟大学Niigata University博士（医学）Background: Sunitinib therapy for patients with imatinib-resistant and/or intolerant gastrointestinal stromal tumors (GISTs) often causes severe adverse events (AEs) that lead to treatment discontinuation. Methods: We retrospectively reviewed the clinical records of imatinib-resistant and/or intolerant GIST patients who underwent sunitinib therapy in our institutions between 2007 and 2020. Forty-one patients were enrolled and divided into two groups on the basis of the starting dosage: the standard dosage group (50 mg/day, 21 patients) and the reduced dosage group (37.5 mg/day, 20 patients). Tolerability, safety and clinical efficacy of the two groups were compared. Results: Three patients (14%) in the standard dosage group and another three (15%) in the reduced dosage group (P=1.000) discontinued sunitinib therapy because of AEs. The incidences of grade 3 or more severe treatment-related AEs were 90 and 75%, respectively (P=0.238). Two possible treatment-related deaths were noted in the standard dosage group. Clinical efficacy was comparable between the two groups: median time to treatment failure and overall survival were 4.5 months [interquartile range (IQR), 3.6-9.0] and 13.7 months (IQR, 7.5-22.9) in the standard dosage group and 4.6 months (IQR, 2.7-17.0) and 13.4 months (IQR, 9.3-36.8) in the reduced dosage group, respectively. Conclusions: The reduced dosage of 37.5 mg sunitinib tended to decrease toxicity and the incidences of severe AEs and treatment-related deaths. This reduced dosage regimen showed equivalent clinical efficacy including patient survival. The reduced dosage of 37.5 mg sunitinib can be adopted as an alternative therapy for patients with imatinib-resistant and/or intolerant GISTs.Japanese Journal of Clinical Oncology. 2023, 53(4), 297-303.新大院博(医)第1114
Epidemiologic research about Long-term prognosis of patients treated with endovascular aneurysm repair for aortic disease
Get PDF新潟大学Niigata University博士（医学）[背景]大動脈疾患の多くは無症状で経過する疾患であり、唯一のエンドポイントである大動脈破綻を回避することができれば大動脈疾患がその後の患者の生命予後を規定しないものと考えることができる。一方で大動脈疾患を罹患した症例では様々な基礎疾患を有することが多く、治療により大動脈破綻を回避したとしても、併存疾患により予後が規定されることで健常人に比べて生命予後が不良であることが予想される。しかしこれまで原病死を避け得た場合の長期予後や転機に関する詳細な報告はない。その一因として従来の治療法である開胸・開腹による人工血管置換術の侵襲の大きさが考えられる。一方、近年普及を認めるステントグラフト治療は低侵襲な治療方法であり、患者予後への影響が少ない。大動脈瘤にたいしステントグラフト治療を行った患者を対象として大動脈疾患を罹患した症例が原病死を避け得た場合の長期予後を調査する。[方法]当科でステントグラフト内挿術を施行した1062例を対象として転帰および死亡原因を調査した。原病関連死症例や長期入院症例を除外した782例に対しKaplan-Meier法による生存時間分析を行った。またそれぞれの症例の背景因子について調査しCox-Hazard分析による多変量解析を行った。[結果]転帰は生存474例(60.6%)、死亡255例(32.6%)であり、予後不明症例は53例(6.8%)であった。平均観察期間は1781日であり、最大観察期間は6313日であった。全死亡における5年生存率は72.8%、10年生存率は47.7%であった。死亡原因では呼吸器疾患による死亡を21%と高率に認めた。予後不良因子として年齢、重複瘤、瘤径、呼吸器疾患、脳疾患、悪性腫瘍、透析、血小板数、スタチン内服が示された。[結論]大動脈疾患を罹患した症例では原疾患の治療を完遂し破綻死を避けることができたとしても、その予後は一般に比べて不良である。生命予後の改善には併存疾患を含めた予防や治療介入が必要である。新大院博(医)第1123
薬剤誘導を行ったナイーブ型iPS細胞は、プライム型iPS細胞に比較して、膵β細胞系への分化能に優れている
Get PDF新潟大学Niigata University博士（歯学）Pluripotent stem cells are classified as naïve and primed cells, based on their in vitro growth characteristics and potential to differentiate into various types of cells. Human-induced pluripotent stem cells (iPSCs, also known as epiblast stem cells [EpiSCs]) have limited capacity to differentiate and are slightly more differentiated than naïve stem cells (NSCs). Although there are several in vitro protocols that allow iPSCs to differentiate into pancreatic lineage, data concerning generation of β-cells from these iPSCs are limited. Based on the pluripotentiality of NSCs, it was hypothesized that NSCs can differentiate into pancreatic β-cells when placed under an appropriate differentiation induction condition. We examined whether NSCs can be efficiently induced to form potentially pancreatic β-cells after being subjected to an in vitro protocol. Several colonies resembling in vitro-produced β-cell foci, with β-cell-specific marker expression, were observed when NSC-derived embryoid bodies (EBs) were induced to differentiate into β-cell lineage. Conversely, EpiSC-derived EBs failed to form such foci in vitro. Intrapancreatic grafting of the in vitro-formed β-cell foci into nude mice (BALB/c-nu/nu) generated a cell mass containing insulin-producing cells (IPCs), without noticeable tumorigenesis. These NSCs can be used as a promising resource for curing type 1 diabetes.Journal of Climinal Medicine. 2020, 9(9), 2838.新大院博(歯)第523
The effect of heavy ion irradiation on three-dimensional in vitro models of normal oral mucosa and oral cancer : Development of standardized system to evaluate different irradiation therapies
Get PDF新潟大学Niigata University博士（歯学）新大院博(歯)第530
An Examination of the Effect of the Care provided in Foster Homes : A Comparison between the Assessments of the children in Foster Homes Utilizing the Child Behavior Checklist (CBCL) and the "New Vision for Alternative Care and the Role of Society in Child Well-being"
Get PDF新潟大学Niigata University博士（学術）本論では児童養護施設のケア効果について，主に「新しい社会的養育ビジョン」に挙げられる要因との関連，つまり，児童養護施設でのケアの規模，入所時点での児童の年齢，入所期間，入所施設の変更の有無によって，現在の入所児童の情緒と行動の問題に差が見られるかを検討した．調査対象は，関東甲信越地域のA県内の全児童養護施設5施設の入所児童164人とし，対象児童を担当する職員から「Child Behavior Checklist(CBCL)」に回答してもらい，その総尺度得点とこれらの要因と関連を検討した．結果，統計的に有意な関連が認められたのは，ケア規模のみであり，その他の要因によるCBCL総尺度得点への影響は確認できなかった．これらの結果から，児童養護施設におけるケアの効果については，社会的養育ビジョンに示される要因だけでなく，さらに広くほかの要因も含めて検討していく必要性を考察した．In this study, the effect of the care provided in foster homes was primarily examined in the context of the "New vision for alternative care and the role of society in child well-being." Namely, the differences in the emotional and behavioral problems that children showed in these institutions were considered in terms of several factors, including the scale of the care unit, the age at which the child entered the unit, the duration of the care, and the changes of the institutions wherein they were cared for. The subjects of this study were 164 children, cared for in 5 foster homes in a prefecture of the Kanto-Koshinetsu region. The care workers in charge of them completed a Child Behavior Checklist (CBCL). Then the relationship between the CBCL total scale score and the abovementioned factors were examined. A statistically significant relationship was found only for the scale of the care unit, but the influence of other factors on the CBCL total standard score could not be confirmed. From these results, we considered that the effect of the care in the foster homes must be examined, including other factors besides the factors stated in the "New vision for alternative care and the role of society in child well-being."社会福祉学. 2021, 62(1), 27-37.新大院博(学)第40
大豆ペプチドは殺菌的作用により歯周病原細菌バイオフィルム形成を阻害する
Get PDF新潟大学Niigata University博士（歯学）Objective: This study aimed to clarify the antibacterial mechanism and antibiofilm effect of soybean-derived peptide BCBS-11 against periodontopathic bacteria. Design: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of BCBS-11 against Porphyromonas gingivalis (P. gingivalis), Fusobacterium nucleatum (F. nucleatum), and Streptococcus mitis (S. mitis) were determined for the antibacterial mechanism. The effect of BCBS-11 on membrane permeability and depolarization activity were investigated using propidium iodide (PI) staining and 3, 3'-dipropylthiadicarbocyanine iodide (DiSC3-(5)) analysis. Monospecies and multispecies biofilms were cultured on 96-well plates. The amount of biofilm was determined using crystal violet staining to determine the inhibition of biofilm formation and the eradication of established biofilm using BCBS-11. The cytotoxicity of BCBS-11 was evaluated using 3-(4, 5-Dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay. Results: The MIC and MBC indicated the bactericidal activity of BCBS-11 against P. gingivalis and F. nucleatum. The PI staining revealed that BCBS-11 disrupted the bacterial membrane integrity. The DiSC3-(5) analysis indicated that BCBS-11 depolarized the bacterial cytoplasmic membrane. These results indicate the antimicrobial action of BCBS-11 through membrane disruption and the collapse of membrane electrochemical gradient. BCBS-11 significantly inhibited the monospecies biofilm formation of P. gingivalis and F. nucleatum and also inhibited dual-species biofilm. BCBS-11 was not cytotoxic toward human oral epithelial cells. Conclusions: BCBS-11 inhibits the monospecies and multispecies biofilm formation of P. gingivalis and F. nucleatum, and their bactericidal activity results from membrane disruption.Archives of Oral Biology. 2022, 142, 105497.新大院博(歯)第546
2-パルミトイルグリセロールはヒト胎児由来アストロサイトにてγ-アミノ酪酸の産生を促進する
Get PDF新潟大学Niigata University博士（医学）Breast milk contains constituents, such as 1, 3-dioleoyl-2-palmitoylglycerol (OPO), that are beneficial for infants. Herein, we hypothesized that 2-palmitoyl glycerol (2-PG), a derivative of OPO, is advantageous to infants’development. Gamma aminobutyric acid (GABA) is a major neurotrans-mitter involved in neural development. Although GABA is generally known to be produced in neurons, astrocytes can also produce it in imma-ture brains. In this study, we used expression analysis techniques to show that 2-PG upregulates the mRNA and protein expression of glutamate dec-arboxylases(GAD1 and GAD2) in normal human fetal-derived astrocytes.Our data suggest that 2-PG promotes GABA synthesis in astrocytes, which may contribute to brain development because GABA is involved in neural development in the developing brain. This may help to elucidate the mech-anism by which breast milk affects infant brain development.FEBS Open Bio. 2023, 13(7), 1320-1332.新大院博（医）第1139
家族性大腸腺腫症における胃腫瘍の内視鏡的特徴と内視鏡治療についての検討
Get PDF新潟大学Niigata University博士（医学）Purpose: Gastric neoplasia is a common manifestation of familial adenomatous polyposis (FAP). This study aimed to elucidate the clinical characteristics, endoscopic features including fundic gland polyposis (FGPsis), an treatment outcomes of gastric neoplasms (GNs) in patients with FAP. Materials and Methods: A total of 35 patients diagnosed with FAP, including nine patients from four pedigrees who underwent esophagogastroduodenoscopy (EGD), were investigated regarding patient characteristics, GN morphology, and treatment outcomes. Results: Twenty-one patients (60.0%) had 38 GNs; 33 (86.8%) and 5 (13.2%) were histologically diagnosed with adenocarcinoma and adenoma, respectively. There were no specific patient characteristics related to GNs.Nodule-type GNs were more prevalent in patients with FGP than without (52.2% vs. 0.0%, P=0.002) in the upper body of the stomach. Conversely, depressed-type GNs were fewer in patients with FGPsis than in those without (13.0% vs. 73.3%, P<0.001). Slightly elevated-type GNs were observed in both groups (34.8% vs. 20.0%, P=0.538). Even within pedigrees, the background gastric mucosa and types of GNs varied. In total, 24 GNs were treated with endoscopic submucosal dissection (ESD) and eight with endoscopic mucosal resection (EMR). EMR was selected for GNs with FGPsis because of the technical difficulty of ESD, resulting in a lower en bloc resection rate (62.5% vs. 100%, P=0.014). Conclusions: Our study indicates the necessity of routine EGD surveillance in patients diagnosed with FAP. Notably, the morphology and location of GNs differed between patients with and without FGPsis. Endoscopic treatment and outcomes require more attention in cases of FGPsis.Journal of Gastric Cancer. 2022, 22(4), 381-394.新大院博（医）第1142
ICRおよびNOD/Shiマウスにおけるカドヘリン23の加齢性難聴アレルによる難聴の重篤度の影響
Get PDF新潟大学Niigata University博士（医学）The age-related hearing loss allele (Cdh23ahl) of the cadherin 23 gene leads to a more severe hearing loss phenotype through additive effects with risk alleles for hearing loss. In this study, we genome edited the Cdh23ahl allele to the wild-type Cdh23+ allele in outbred ICR mice and inbred NOD/Shi mice established from ICR mice and investigated their effects on hearing phenotypes. Several hearing tests confirmed that ICR mice developed early onset high-frequency hearing loss and exhibited individual differences in hearing loss onset times. Severe loss of cochlear hair cells was also detected in the high-frequency areas in ICR mice. These phenotypes were rescued by genome editing the Cdh23ahl allele to Cdh23+, suggesting that abnormal hearing phenotypes develop because of the interaction of the Cdh23ahl and risk alleles in the genetic background of ICR mice. NOD/Shi mice developed more severe hearing loss and hair cell degeneration than ICR mice. Hearing loss was detected at 1 month old. Hair cell loss, including degeneration of cell bodies and stereocilia, was observed in all regions of the cochlea in NOD/Shi mice. Although these phenotypes were partially rescued by genome editing to the Cdh23+ allele, the phenotypes associated with high-frequency hearing were mostly unrecovered in NOD/Shi mice. These results strongly suggest that the genetic background of NOD/Shi mice contain a potential risk allele for the acceleration of early onset high-frequency hearing loss.Biochemical and Biophysical Research Communications, 2023, 674, 147-153.新大院博（医）第1143