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Two cases of 46,XY differences/disorders of sex development in patients with inguinal hernia
Get PDF46,XY性分化疾患（differences/disorders of sex development : DSD）は，46,XYの核型をもつ性分化疾患であり，性腺，内外性器に様々な程度の男性化障害を認める．社会的に女性として養育されていた児において，腹腔鏡下鼠径ヘルニア手術の際に精巣を指摘され，46,XY DSDの診断に至った2症例を報告する．2例とも会陰部に膣を認め，その直上に尿道が開口しており，女性型外性器を呈していた．症例1（0歳6か月）は子宮は認めず，両側鼠径部に精巣を有し，十分なテストステロン分泌が認められた．症例2（1歳8か月）は，陰核肥大と左鼠径部に精巣を有し，低形成の子宮を認めた．hCG負荷試験にてテストステロンの上昇を認めた．以上より，いずれの症例も胎児期に脳がアンドロゲン暴露を受けた可能性を有するため，性自認の確認が必要と考えられた．
女児の鼠経ヘルニアの診察時にはDSDを念頭におく必要があり，DSDを疑った場合には，慎重な精査と包括的対応が必要となる．journal articl
CD109 on dendritic cells regulates airway hyperreactivity and eosinophilic airway inflammation
Get PDF浜松医科大学博士（医学）doctoral医学系研究科thesi
Association between social activity and development of dementia in hearing impairment: A cohort study in Japan from Japan Gerontological Evaluation Study
Get PDF浜松医科大学博士（医学）doctoral医学系研究科thesi
UBL3 interaction with α-synuclein is downregulated by silencing MGST3
Get PDF浜松医科大学博士（医学）doctoral医学系研究科thesi
Assessments of therapeutic effects according to timings for combined therapy with axitinib and immune check point inhibitor in a mouse renal cell carcinoma model
Get PDF浜松医科大学博士（医学）doctoral医学系研究科thesi
Efficacy of HSV-TK/GCV system suicide gene therapy using SHED expressing modified HSV-TK against lung cancer brain metastases
Get PDF浜松医科大学博士（医学）dotoral医学系研究科Lung cancer is one of the most common cancers, and the number of patients with intracranial metastases is increasing. Previously, we developed an enzyme prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) system using various mesenchymal stem cells to induce apoptosis in malignant gliomas through bystander killing effects. Here, we describe stem cells from human exfoliated deciduous teeth (SHED) as gene vehicles of the TK/GCV system against a brain metastasis model of non-small cell lung cancer (NSCLC). We introduced the A168H mutant TK (TKA168H) into SHED to establish the therapeutic cells because of the latent toxicity of wild type. SHED expressing TKA168H (SHED-TK) exhibited chemotaxis to the conditioned medium of NSCLC and migrated toward implanted NSCLC in vivo. SHED-TK demonstrated a strong bystander effect in vitro and in vivo and completely eradicated H1299 NSCLC in the brain. SHED-TK cells implanted intratumorally followed by GCV administration significantly suppressed the growth of H1299 and improved survival time. These results indicate that the TKA168H variant is suitable for establishing therapeutic cells and that intratumoral injection of SHED-TK followed by GCV administration may be a useful strategy for therapeutic approaches.doctoral thesi
Astrocytic NKCC1 inhibits seizures by buffering Cl- and antagonizing neuronal NKCC1 at GABAergic synapses
Get PDF浜松医科大学博士（医学）doctoral医学系研究科A pathological excitatory action of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl⁻ importer NKCCl with bumetanide is expected to reduce the neuronal intracellular Cl⁻ concentration ([Cl⁻]i) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy are currently ongoing. Although NKCCl is expressed in both neurons and glial cells, an involvement of glial NKCCl in seizures has not yet been reported. Astrocytes maintain high [Cl⁻]i with NKCCl, and this gradient promotes Cl⁻ efflux via the astrocytic GABAA receptor (GABAAR). This Cl⁻ efflux buffers the synaptic cleft Cl⁻ concentration ([Cl⁻]o) to maintain the postsynaptic Cl⁻ gradient during intense firing of GABAergic neurons, thereby sustaining its inhibitory action during epilepsy. In this study, we investigated the function of astrocytic NKCCl in modulating the postsynaptic action of GABA in acute seizure models. We used the astrocyte-specific NKCCl knockout (AstroNKCClKO) mice. Seizure-like events (SLEs) in CAI pyramidal neurons in vitro and in the in vivo pilocarpine-induced seizure model were evaluated. The AstroNKCClKO mice were prone to seizures with lower threshold and longer duration of SLEs and larger GABAAR-mediated depolarization underlying the SLEs, accompanied by higher Racine-scored seizures. Bumetanide reduced these indicators of seizure in AstroNKCClKO mice (which still express neuronal NKCCl), but not in the WT, both in vitro and in vivo. Thus, astrocytic NKCCl inhibits excitatory GABA-mediated seizures, whereas neuronal NKCCl has the converse effect, suggesting opposing actions of bumetanide on these cells.doctoral thesi
Role of hepcidin upregulation and proteolytic cleavage of ferroportin 1 in hepatitis C virus-induced iron accumulation
Get PDF浜松医科大学博士（医学）doctoral医学系研究科Hepatitis C virus (HCV) is a pathogen characterized not only by its persistent infection leading to the development of cirrhosis and hepatocellular carcinoma (HCC), but also by metabolic disorders such as lipid and iron dysregulation. Elevated iron load is commonly observed in the livers of patients with chronic hepatitis C, and hepatic iron overload is a highly profibrogenic and carcinogenic factor that increases the risk of HCC. However, the underlying mechanisms of elevated iron accumulation in HCV-infected livers remain to be fully elucidated. Here, we observed iron accumulation in cells and liver tissues under HCV infection and in mice expressing viral proteins from recombinant adenoviruses. We established two molecular mechanisms that contribute to increased iron load in cells caused by HCV infection. One is the transcriptional induction of hepcidin, the key hormone for modulating iron homeostasis. The transcription factor cAMP-responsive element-binding protein hepatocyte specific (CREBH), which was activated by HCV infection, not only directly recognizes the hepcidin promoter but also induces bone morphogenetic protein 6 (BMP6) expression, resulting in an activated BMP-SMAD pathway that enhances hepcidin promoter activity. The other is post-translational regulation of the iron-exporting membrane protein ferroportin 1 (FPN1), which is cleaved between residues Cys284 and Ala285 in the intracytoplasmic loop region of the central portion mediated by HCV NS3-4A serine protease. We propose that host transcriptional activation triggered by endoplasmic reticulum stress and FPN1 cleavage by viral protease work in concert to impair iron efflux, leading to iron accumulation in HCV-infected cells.Author summary
Iron plays an important role in many biological processes, including cell proliferation and metabolism, and disruption of iron homeostasis leads to the generation of harmful reactive oxygen species through the Fe2+-triggered Fenton/Haber-Weiss reaction. Iron deposition is often observed in liver tissues of chronic hepatitis C patients, and it has been considered that abnormal iron metabolism is potentially involved in the pathogenesis of HCV. In this study, we show that, in the hepcidin-ferroportin axis, the key mechanism involved in regulation of iron homeostasis, both induction of hepcidin expression and proteolytic cleavage of ferroportin 1 protein induced by HCV infection lead to increased iron levels in the cells, and identify viral factors responsible for the iron accumulation. This is the first study to demonstrate that two mechanisms, transcriptional activation of host cells upon pathogen infection and host protein cleavage by pathogen-derived proteases, work together to result in iron accumulation in host cells. These findings not only deepen our understanding of the mechanisms of HCV-related pathologies, but also lead to the development of new therapies for chronic liver diseases.doctoral thesi
HPV vaccine
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・HPVに関連する悪性腫瘍は，子宮頸癌のみでなく，口腔咽頭癌，直腸癌，肛門癌などがあり，男女に共通した問題である．
・2023年1月現在，時限的ではあり年齢制限もあるが，キャッチアップ接種でも公費助成が受けられる．
・被接種側と接種側の双方によるワクチンに関わる理解が，接種環境を向上させる一因となると考えられている．journal articl