Niigata University Medical and Dental Hospital
Niigata University Academic RepositoryNot a member yet
33813 research outputs found
Sort by
同位体比測定を用いた森林小集水域における硫黄動態の推定
Get PDF新潟大学Niigata University博士（農学）東アジア地域においては，1980 年代以降の急速な経済発展により，人為由来の大気汚染物質の排出量が著しく増大しており，土壌と陸水の酸性化が引き起こされている。こういった背景から，大気沈着に含まれる物質の森林生態系への影響を評価することを目的として，2002 年から新潟県新発田市（旧加治川村）のスギ人工林に設定した小集水域において，各種物質の沈着量および流出量のモニタリング調査が実施されている。二酸化硫黄や硫酸などの硫黄化合物は，土壌-植物系での保持/放出プロセスにおいて，水素イオンを伴うことが多いため，森林生態系の酸性化に大きな役割を果たしており，森林生態系に蓄積された硫黄を放出するタイミングおよびメカニズムについては非常に注目されている。そのため，2012年以降は上記の調査に加え，大気沈着硫黄の森林生態系内での動態を明らかにすることを目的として，硫黄同位体比（δ34S）測定を用いた調査を実施した。石油や石炭などの化石燃料に含まれる硫黄化合物は，産出国や地域によって同位体比が異なり，それらの同位体比の違いは降水や粒子状物質などの大気沈着に反映されるため，δ34S は，大気環境における硫黄の起源や森林生態系における硫黄の挙動を調査するための有用なツールとしてよく用いられている。また，生態系内での硫黄循環/流出過程に対する植物系の役割を推定するため，主要樹種であるスギのリターフォールを対象に，硫黄循環量および硫黄同位体比の調査を実施した。さらに，硫黄循環の周期が短い一年生草本を含む下層植生に着目し，森林生態系における硫黄循環に対する下層植生の役割の評価もあわせて行った。 大気沈着に由来する酸性物質，特に硫黄化合物は， 森林生態系の酸性化に大きく寄与しており，歴史的に越境大気汚染に悩まされてきた中部日本の森林集水域では，冬季に大陸からの北西の季節風により，大気硫黄フラックスが大幅に増加していた。海塩と越境大気汚染の影響が大きいため，寒候期と温暖期では大気沈着によるフラックスはそれぞれ 1.0 および 0.3 kmolc ha–1 であった。大気沈着には大きな季節性があるにもかかわらず，渓流水中の硫酸イオン濃度は年間を通して比較的安定していた。同様に，降水中のδ34S は明確な季節変動を示し，冬には最大 13‰ まで増加し，夏には 3‰ まで減少したが，渓流水では約 9‰で安定していた。降水，林内雨，樹幹流および渓流水における加重平均 δ34S 値には大きな差はなく，それぞれ 8.5，9.5，9.0 および 9.0‰ となっていた。降水および土壌溶液中の δ34S と硫酸イオン濃度の逆数の間には線形関係は見られず，いずれも渓流水の値に向けて収束しており，生態系内部にエンドメンバーとなる特定の硫黄源がないことが示唆された。植物系における硫黄循環に関する調査からは，2012 年から 2016 年までの硫黄沈着量平均 23 kg S ha–1 yr–1 に対し，リターフォールを介しての硫黄循環量は約 11%，下層植生としては約 7% に相当するという結果が得られた。リターフォールおよび下層植生による生物学的硫黄循環が比較的小さいということが示され，土壌表面における硫酸イオンの吸着/脱着が主に季節的な大量の硫黄の流入を緩衝し，急激な酸性化を防いでいることが示唆された。気候変動下において，このような緩衝システムがどのように挙動するのか注視する必要があると考えられる。 森林生態系における硫黄循環は，今後大気沈着量が低下し続ける中，酸性環境からの回復過程を支配する重要な因子の一つであり，引き続き調査研究が行われるべきである。In East Asia, rapid economic development since the 1980s has significantly increased emissions of anthropogenic air pollutants, causing acidification of soil and inland water. Against this background, in order to evaluate the impact of substances contained in atmospheric deposition on forest ecosystems, we have been conducting research since 2002 in a small watershed established in a cedar plantation in Shibata City, Niigata Prefecture (formerly Kajikawa Village)., monitoring surveys of the amount of deposition and outflow of various substances are being conducted. Sulfur compounds such as sulfur dioxide and sulfuric acid play a major role in the acidification of forest ecosystems because they are often accompanied by hydrogen ions during retention/release processes in the soil-plant system, and they accumulate in forest ecosystems. The timing and mechanism of sulfur release are of great interest. Therefore, since 2012, in addition to the above survey, we have conducted a survey using sulfur isotopic ratio (δ34S) measurements with the aim of clarifying the dynamics of atmospherically deposited sulfur within forest ecosystems. Sulfur compounds contained in fossil fuels such as oil and coal have different isotopic ratios depending on the country and region where they are produced, and these differences in isotopic ratios are reflected in atmospheric deposition such as precipitation and particulate matter, so δ34S is, it is often used as a useful tool to investigate the origin of sulfur in the atmospheric environment and the behavior of sulfur in forest ecosystems. In addition, in order to estimate the role of plant systems in the sulfur circulation/runoff process within the ecosystem, we conducted a survey of sulfur circulation amount and sulfur isotopic ratio in the litterfall of Japanese cedar, a major tree species. Furthermore, we focused on understory vegetation, including annual herbs, which have short sulfur cycle cycles, and also evaluated the role of understory vegetation on sulfur cycling in forest ecosystems. Acidic substances, especially sulfur compounds, derived from atmospheric deposition greatly contribute to the acidification of forest ecosystems, and forest catchments in central Japan, which have historically suffered from transboundary air pollution, are affected by air pollution from the continent during the winter. The atmospheric sulfur flux was significantly increased due to the northwesterly monsoon. Due to the large influence of sea salt and transboundary air pollution, the fluxes due to atmospheric deposition were 1.0 and 0.3 kmolc ha–1 during the cold and warm seasons, respectively. Despite significant seasonality in atmospheric deposition, sulfate ion concentrations in mountain stream water remained relatively stable throughout the year. Similarly, δ34S in precipitation showed clear seasonal fluctuations, increasing up to 13‰ in winter and decreasing to 3‰ in summer, but remained stable at about 9‰ in mountain stream water. There was no significant difference in the weighted average δ34S values for precipitation, forest rain, tree trunk flow, and mountain stream water, which were 8.5, 9.5, 9.0, and 9.0‰, respectively. There is no linear relationship between δ34S in precipitation and soil solution and the reciprocal of sulfate ion concentration, and both converge toward the value of mountain stream water, indicating that there is a specific sulfur source that is an end member within the ecosystem. It was suggested that there is no. A study on sulfur cycling in plant systems revealed that from 2012 to 2016, the average sulfur deposition amount was 23 kg S ha–1 yr–1, but the sulfur cycling amount via litterfall was approximately 11%, and as for the understory vegetation. The results show that this is equivalent to approximately 7%. It has been shown that biological sulfur cycling by litterfall and understory vegetation is relatively small, and the adsorption/desorption of sulfate ions at the soil surface mainly buffers the large seasonal sulfur influx and prevents rapid acidification. It was suggested that it was prevented. It is necessary to pay close attention to how such buffer systems behave under climate change. The sulfur cycle in forest ecosystems is one of the important factors governing the recovery process from acidic environments as atmospheric deposition continues to decline, and research and investigation should continue.新大博(農)第33
SLFN11 は卵巣高異型度漿液性癌および明細胞癌においてBRCAと独立したプラチナ感受性予測バイオマーカーである
Get PDF新潟大学Niigata University博士（医学）BRCA1/2 mutations are robust biomarkers for platinum-based chemotherapy in epithelial ovarian cancers. However, BRCA1/2 mutations in clear cell ovarian carcinoma (CCC) are less frequent compared to high-grade serous ovarian cancer (HGSC). The discovery of biomarkers that can be applied to CCC is an unmet need in chemotherapy. Schlafen 11 (SLFN11) has attracted attention as a novel sensitizer for DNA-damaging agents including platinum. In this study, we investigated the utility of SLFN11 in HGSC and CCC for platinum-based chemotherapy. SLFN11 expression was analyzed retrospectively by immunohistochemistry across 326 ovarian cancer samples. The clinicopathologic significance of SLFN11 expression was analyzed across 57 advanced HGSC as a discovery set, 96 advanced HGSC as a validation set, and 57 advanced CCC cases, all of whom received platinum-based chemotherapy. BRCA1/2 mutation was analyzed using targeted-gene sequencing. In the HGSC cohort, the SLFN11-positive and BRCA mutation group showed significantly longer while the SLFN11-negative and BRCA wild-type group showed significantly shorter progression-free survival and overall survival. Moreover, SLFN11- positive HGSC shrunk significantly better than SLFN11-negative HGSC after neoadjuvant chemotherapy. Comparable results were obtained with CCC but without consideration of BRCA1/2 mutation due to a small population. Multivariate analysis identified SLFN11 as an independent factor for better survival in HGSC and CCC. The SLFN11-dependent sensitivity to platinum and PARP inhibitors were validated with genetically modified non-HGSC ovarian cancer cell lines. Our study reveals that SLFN11 predicts platinum sensitivity in HGSC and CCC independently of BRCA1/2 mutation status, indicating that SLFN11 assessment can guide treatment selection in HGSC and CCC.Molecular cancer therapeutics. 2024, 23(1), 106-116.新大院博（医）第1161
局所脳虚血病巣から離れた遠隔領域における軸索損傷はヘルニアによる虚血範囲の拡大によって生じる
Get PDF新潟大学Niigata University博士（医学）Cerebral ischemia may lead to axonal injury not only at the site of the primary lesion but also in a region remote to the site of insult. In this study, we investigated the effect of herniation on the development of axonal injury in a site remote to the primary lesion during the acute phase of cerebral ischemia. We obtained post-mortem brains of 13 cases with acute phase of unilateral cerebral infarction in the territory of the internal carotid artery or middle cerebral artery and seven controls. We classified the brain tissues into the herniation and non-herniation groups. Then, we examined whether axonal and ischemic changes exist in the corpus callosum contralateral to the ischemic hemisphere and the upper pons. In the herniation group, we detected white matter lesions by Klüver-Barrera staining, microglial loss by immunohistochemistry for ionized calcium-binding adaptor molecule 1, and axonal injury by immunohistochemistry for amyloid precursor protein. However, none of the aforementioned findings were observed in the non-herniation group. These findings suggest the existence of regional overlap in axonal and ischemic pathologies in remote regions in the presence of herniation. We concluded that herniation may play a significant role in the development of axonal and ischemic changes in the remote region. Our results suggest that axonal injury in the remote region may result from expanded ischemic lesions due to herniation.Neuropathology. 2023, 43(5), 373-384.Published source is the following：Seki, E., Komori, T. and Arai, N. (2023), Expanded ischemic lesion due to herniation leads to axonal injury in a site remote to the primary lesion on autopsy brain with acute focal cerebral ischemia. Neuropathology, 43: 373-384. https://doi.org/10.1111/neup.12900新大院博（医）第1167
日本人の両心室ペーシング機能付き植え込み型除細動器(CRT-D)治療後の心機能の低下した心不全患者における長期生存予測因子
Get PDF新潟大学Niigata University博士（医学）Background: Reports on the factors predicting long-term survival ofCRT-D cases from Western countries are increasing, however, those from Asia including Japan are still sparse.We aimed to clarify the factors predicting long-term survival of Japanese CRT-D cases. Methods: We retrospectively analyzed consecutive 133 patients who underwent CRT-D implantation between 2006 and 2021.We compared clinical factors between patients who died within 5 years after implantation (short-survival group: n = 31) and who had survived for more than 5 years (long-survival group: n = 36) after implantation. Results: Major underlying heart diseases were dilated cardiomyopathy (45%) and ischemic heart disease (12%). There was no difference between the short-survival group and the long-survival group in incidence of CLBBB (32% vs. 30%), whereas CRBBB was more common in the short-survival group (26% vs. 0%, p = .004).Mechan-ical dyssynchrony at implantation was more frequent in the long-survival group (48% vs. 78%, p = .02). The incidence of response to CRT at 1 year after implantation was higher in long-survival group (19% vs. 50%, p = .02). Multiple logistic regression analysis identified NYHA class, mechanical dyssynchrony at implantation, and response at one year as predictors of long-term survival. Conclusions: In Japanese CRT-D cases, lower NHYA class, preexisting mechanical dyssynchrony, and 1-year response to CRT predict long-term survival.This is the peer reviewed version of the following article: Sakaguchi Y, Izumi D, Wada R, et al. Predictors of long-term survival in Japanese patients with heart failure with reduced ejection fraction (HFrEF) treated with cardiac resynchronization therapy-defibrillators (CRT-D). Pacing Clin Electrophysiol. 2023; 46: 1484–1490., which has been published in final form at https://doi.org/10.1111/pace.14848. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.新大博（医）第1195
脂肪肝を予防するためのインスリン様成長因子‐1活性化における末梢神経系と中枢神経系の相補的役割
Get PDF新潟大学Niigata University博士（医学）Background Insulin-like growth factor-1 (IGF-1) is involved in the pathology of non-alcoholic fatty liver disease (NAFLD) and ameliorates fatty infiltration in the liver. It is activated by growth hormone (GH); however, the role of GH–IGF-1 axis in NAFLD developmental phase has not been well identified. Therefore, in this study, we focused on the effect of IGF-1 in NAFLD pathology and GH excretion activation from the pituitary gland by peripheral autonomic neural pathways relaying liver–brain–gut pathway and by central neuropeptides. Methods GH and IGF-1 levels were assessed in wild-type and melanocortin-4 receptor knockout mice upon the develop-ment of diet-induced NAFLD. The contribution of the peripheral autonomic nervous system connecting the liver–brain–gut axis was assessed by its blockade using capsaicin and that of the central nervous system was assessed by the expression of hypothalamic brain-derived neurotrophic factor (BDNF) and corticotropin-releasing factor (CRH), which activates GH release from the pituitary gland. Results In the NAFLD mouse models, the levels of GH and IGF-1 increased (p < .05). Further, hepatic fatty infiltration was suppressed even under peripheral autonomic nervous system blockade (p < .001), which inhibited gastric ghrelin expression. In mice with peripheral autonomic nervous blockade, hypothalamic BDNF and CRH were inhibited (p < .05), resulting in GH and IGF-1 excretion, whereas other neuropeptides of somatostatin and cortistatin showed no changes. These complementary effects were canceled in melanocortin-4 receptor knockout mice, which diminished BDNF and CRH release control. Conclusions Our study demonstrates that the release of IGF-1 by the nervous system is a key factor in maintaining the pathological homeostasis of NAFLD, suggesting its therapeutic potential.新大院博（医）第1207
胃の進行期腺癌における特異的糖鎖TRA-1-60の病理学的および生物学的意義
Get PDF新潟大学Niigata University博士（医学）The glycans form a unique complex on the surface of cancer cells and play a pivotal role in tumor progression, impacting proliferation, invasion, and metastasis. TRA-1-60 is a glycan that was iden-tified as a critical marker for the establishment of fully reprogrammed inducible pluripotent stem cells. Its expression has been detected in multiple cancer tissues, including embryonal carcinoma, prostate cancer, and pancreatic cancer, but the biological and pathological characterization of TRA-1-60-expressing tumor cells remains unclear within various types of malignancies. Here, we report the biological characteristics of TRA-1-60-expressing gastric cancer cells, especially those with its cell surface expression, and the therapeutic significance of targeting TRA-1-60. The cells with cell membrane expression of TRA-1-60 were mainly observed in the invasive area of patient gastric cancer tissues and correlated with advanced stages of the disease based on histopathological and clinicopathological analyses. In vitro analysis using a scirrhous gastric adenocarcinoma line, HSC-58, which highly expresses TRA-1-60 on its plasma membrane, revealed increased stress-resistant mechanisms, supported by the upregulation of glutathione synthetase and NCF-1 (p47phox) via lipid-ROS regulatory pathways, as detected by RNA-seq analysis followed by oxidative stress gene profiling. Our in vivo therapeutic study using the TRA-1-60-targeting antibody-drug conjugate, namely, Bstrongomab-conjugated monomethyl auristatin E, showed robust efficacy in a mouse model of peritoneal carcinomatosis induced by intraperitoneal xenograft of HSC-58, by markedly reducing massive tumor ascites. Thus, targeting the specific cell surface glycan, TRA-1-60, shows a significant therapeutic impact in advanced-stage gastric cancers.Ayaka Mitsui, Hidekazu Iioka, Yiwei Ling, Shujiro Okuda, Akira Kurose, Michael Schopperle, Tomoko Kondo, Masakiyo Sakaguchi, Ken Saito, Eisaku Kondo,
Pathological and Biological Significance of the Specific Glycan, TRA-1-60, on Aggressive Gastric Adenocarcinoma,
Laboratory Investigation,
Volume 104, Issue 7,
2024,
102073,
ISSN 0023-6837,
https://doi.org/10.1016/j.labinv.2024.102073.
(https://www.sciencedirect.com/science/article/pii/S0023683724017513)新大院博（医）第1208
Elucidation of the interrelationships of molecular markers related to novel therapeutic agents in triple negative breast cancer
Get PDF新潟大学Niigata University博士（医学）【 背 景 】 乳癌のサブタイプの 1 つである卜リプルネガティブ乳癌 (Triple Negative Breast Cancer, TNBC)は，最も予後不良なサブタイプであり， 分子背景の解明による薬物療法の確立が必要とされている. 様々な固形癌において，相同組換え修復欠損(Homologous Recombination Deficiency, HRD) 関連遺伝子バリアントは Poly (ADP-Ribose) Polymerase (PARP) 阻害薬の適応を選択するための分子マーカーとして着目されている．Tumor Mutational Burden (TMB)や Programmed cell Death 1 Ligand 1 (PD-L1) は免疫チェックポイント阻害薬(Immune Checkpoint Inhibitor, ICI) のコンパニオン診断薬として臨床応用されている．本研究の目的は，TNBC における HRD 関連遺伝子バリアント，TMB, PD-L1発現を検討し，相互の関連性を明らかにすることである. 【 方 法 】 2010 年から 2019 年までに外科治療を施行した TNBC のうち，435 遺伝子で構成される癌遺伝子パネル検査を実施した 37 例を対象とした. 19の HRD 関連遺伝子 ( ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, XRCC2) におけるバリアントの有無 ， TMB, 抗 PD-L1 抗体 SP142 および 22C3 を用いた免疫組織化学により PD-L1 発現を評価し，分子マーカー相互の関連性を検討した． 【 結 果 】37 例中 15 例 (40.5%)に何らかの HRD 関連遺伝子バリアントを認め，BRCA1 のバリアントの頻度が最も高かった( 5 例，13.5%). HRD 関連遺伝子バリアントを認めた 15 例中 14 例は TMB-High(10 Muts/Mb 以上 ）であった． HRD 関連遺伝子バリアントを認めた症例は，バリアントを認めなかった症例と比較して TMB-High の頻度が高い傾向にあった(93.3% vs. 63.6%, P = 0.056). HRD 関連遺伝子のバリアントを認めた症例は，バリアントを認めなかった症例と比較して TMB スコアが有意に高かった （ 中央値 12.3 Muts/Mb vs. 10.0 Muts/Mb, P = 0.018). HRD 関連遺伝子のバリアントを認めた症例では，PD-L1 ( SP142 ) 発現陽性の頻度が有意に高かった ( 81.8% vs. 31.6%, P = 0.021). PD-L1 ( 22C3 ) 発現との有意な関連は認められなかった ( P = 0.999). HRD 関連遺伝子のバリアントの有無と TMB-High/Low (Cramer's V = 0.34 )，および PD-L1 ( SP142 ) 発現 ( Cramer' s V = 0.48) には中等度の関連を認めた．HRD 関連遺伝子にバリアントを認めた 15 例は TMB-High, PD-L1( SP142 ) 発現陽性，または PD-L1 ( 22C3 ) 発現陽性のいずれかの特徴を有していた．【 結 論 】 TNBC の 40.5%に HRD 関連遺伝子バリアントを認める. HRD 関連遺伝子バリアントを有する TNBC は， TMB-High, PD-L1 発現陽性の頻度が高く，PARP 阻害薬に加え ICI の適応となる可能性が高い．新大院博（医）第1209