生水 真紀夫

Background: Trophoblasts express Toll-like receptor 3 (TLR3). The artificial TLR3 ligand, PolyI:C, induces an inflammatory response in trophoblasts but an endogenous ligand has not been identified. Notably, inflammatory disorders of pregnancy are associated with increased circulating placenta-derived mRNA. Endogenous degraded, uncapped mRNA is recognized by TLR3 in other cell lines. Objective: We tested the hypothesis that plasma-derived mRNA induces an inflammatory response in a trophoblast cell line via TLR3. Methods: Experiments were performed in the human first trimester extravillous trophoblast cell line HTR-8/SV neo. Plasma-derived mRNA was amplified using modified template switching and final in vitro transcription. We compared free mRNA (which favors cell surface interaction) to liposomally encapsulated mRNA (which favors intracellular mRNA delivery). We tested for the specific requirement of TLR3 signaling using siRNA. We tested for involvement of the canonical signaling pathway downstream of TLR3 by measuring NF-κB and IFN regulatory factor transcriptional activity using firefly-luciferase constructs. Results: Free mRNA did not induce RANTES production. In contrast, liposomal mRNA resulted in marked induction of RANTES production (non-stimulated control 3.4 ± 0.6 pg/mL, liposomal mRNA 169.7 ± 26.2 pg/mL, p &lt 0.001), and this RANTES production was abolished by siRNA for TLR3. Downstream of TLR3, liposomal mRNA-induced dose-response NF-κB and IFN regulatory factor transcriptional activity, and IFN beta production. Conclusion: Plasma-derived 5′ uncapped mRNA delivered intracellularly signals to induce NF-κB activation and increase RANTES production via TLR3. © 2011 Elsevier Ltd. All rights reserved.

Context: Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder characterized by gynecomastia. Although cryptic inversions leading to abnormal fusions between CYP19A1 encoding aromatase and its neighboring genes have been identified in a few patients, the molecular basis remains largely unknown. Objective: The objective of the study was to examine the genetic causes and phenotypic determinants in AEXS. Patients: Eighteen affected males from six families participated in the study. Results: We identified three types of heterozygous genomic rearrangements, i.e. a 79,156-bp tandem duplication involving seven of 11 noncoding CYP19A1 exons 1, a 211,631-bp deletion involving exons 2-43 of DMXL2 and exons 5-10 of GLDN, and a 165,901-bp deletion involving exons 2-43 of DMXL2. The duplicated exon 1 functioned as transcription start sites, and the two types of deletions produced the same chimeric mRNA consisting of DMXL2 exon 1 and CYP19A1 coding exons. The DMXL2 exon 1 harbored a translation start codon, and the DMXL2/CYP19A1 chimeric mRNA was identified in only 2-5% of CYP19A1-positive transcripts. This was in contrast to the inversion-mediated chimeric mRNA that had no coding sequence on the fused exon 1 and accounted for greater than80% of CYP19A1-positive transcripts. CYP19A1 was expressed in a limited number of tissues, whereas its neighboring genes involved in the chimeric mRNA formation were expressed widely. Conclusions: This study provides novel mechanisms leading to gain of function of CYP19A1. Furthermore, it appears that clinical severity of AEXS is primarily determined by the tissue expression pattern of relevant genes and by the structural property of promoter-associated exons of chimeric mRNA. Copyright © 2011 by The Endocrine Society.

目的:子宮頸がん検診にベセスダシステム2001を導入し、不適正検体の頻度の実際とその推移について検討を行った。方法:2009年4月から千葉県柏市の子宮頸がん検診にベセスダシステム2001を導入した。2009年4月〜2010年1月までの10ヵ月間に個別検診で採取された検体11090例、および2009年11月〜2010年1月までの3ヵ月間に数人の医師によって行われた車検診による集団検診で採取された4424例の検体について不適正率を調査した。その結果をベセスダシステム2001が導入される以前の2008年1年間の個別検診のデータと比較検討した。すべての検体はちば県民保健予防財団にて診断し、個別検診については1ヵ月ごとに不適正率を各施設に報告した。成績:ベセスダシステム2001導入以前の個別検診における不適正率は0.11%であったのに対して、導入後の個別検診における不適正率は10ヵ月間で1.36%であり、月別には6.25%から0.40%へ時間の経過とともに低下した。また車検診による集団検診では不適正率は0.07%であった。結論:不適正検体の報告を各施設に頻回に行うこと、また、少人数の医師が集中して細胞診の検体採取を行うことが、不適正率の低下に寄与することが示唆された。(著者抄録)

Metastasis of ovarian carcinoma to the small bowel parenchyma without peritoneal dissemination is uncommon. A 63-year-old woman underwent surgery for a clear cell adenocarcinoma of the ovary and received adjuvant chemotherapy. Eighteen months after the operation, she presented with recurrent occult bowel hemorrhage without evidence of an abdominal mass. Nine months later, a rapidly growing abdominal mass was detected. Laparoscopy revealed a solitary tumor of the ileum covered with an intact serosal layer. Partial ileectomy was performed for tumor resection. Histological examination revealed cells resembling the primary ovarian tumor in the mucosal surface of the small bowel along with an intact serosa. The tumor cells were positive for cytokeratin 7 and negative for cytokeratin 20, suggesting an ovarian origin. This is the first report of solitary metastasis of an ovarian carcinoma to the small bowel parenchyma without peritoneal dissemination. Metastasis to the small bowel should be considered in ovarian carcinoma patients with occult gastrointestinal hemorrhage. © 2011 Japan Society of Obstetrics and Gynecology.

アロマターゼはエストロゲン合成に必須の酵素であり、生殖生理機能に重要な役割を果たしている。エストロゲンの作用には、血中を介して遠隔の標的臓器に及ぼす内分泌作用と、末梢組織で合成されてその近傍で作用するパラクリン・オートクリン作用とがある。最近では、卵巣においても後者の役割が注目されている。

Based on the microRNA (miRNA) expression signatures of hypopharyngeal and esophageal squamous cell carcinoma, we found that miR-1 was significantly down-regulated in cancer cells. In this study, we investigated the functional significance of miR-1 in head and neck squamous cell carcinoma (HNSCC) cells and identified miR-1-regulated novel cancer pathways. Gain-of-function studies using miR-1 revealed significant decreases in HNSCC cell proliferation, invasion, and migration. In addition, the promotion of cell apoptosis and cell cycle arrest was demonstrated following miR-1 transfection of cancer cells. A search for the targets of miR-1 revealed that transgelin 2 (TAGLN2) was directly regulated by miR-1. Silencing of TAGLN2 significantly inhibited cell proliferation and invasion in HNSCC cells. Down-regulation of miR-1 and up-regulation of TAGLN2 were confirmed in HNSCC clinical specimens. Our data indicate that TAGLN2 may have an oncogenic function and may be regulated by miR-1, a tumor suppressive miRNA in HNSCC. The identification of novel miR-1-regulated cancer pathways could provide new insights into potential molecular mechanisms of HNSCC carcinogenesis. © Nohata et al.

Aromatase, a key enzyme of estrogen biosynthesis, is transcriptionally regulated by many growth factors. IGF-I enhances aromatase activity in a variety of cells, but the mechanism of action has not been determined. We herein report our finding of a novel mechanism of action for IGF-I. IGF-I enhanced the dexamethasone (DEX)-induced aromatase activity by 30% in serum-starved THP-1 cells. The increase was associated with a corresponding increase in the level of aromatase protein but not with any change in the mRNA level. Metabolic labeling experiments revealed that IGF-I inhibited the degradation of aromatase. We identified pepstatin A as the most effective inhibitor of aromatase degradation by in vitro assay. Using a nontoxic concentration of pepstatin A, we examined IGF-I's action on aromatase distribution in microsomes and lysosomes. In the presence of pepstatin A, DEX caused an increase in the amount of aromatase in both microsomes and lysosomes, and IGF-I attenuated the DEX-induced accumulation of aromatase in lysosomes and, conversely, enhanced its accumulation in the microsomes. The addition of serum abolished the IGF-I-induced changes. The transport from microsome to lysosome was fluorescently traced in cells using a recombinant aromatase. IGF-I selectively reduced the aromatase signal in the lysosomes. Finally, we observed that IGF-I enhanced the aromatase activity by 50% as early as 1 h after treatment; furthermore, rapamycin, an enhancer of autophagy, completely negated the effect of IGF-I on the enzyme. These results indicate that IGF-I enhances aromatase by the inhibition of autophagy. (Endocrinology 151: 4949-4958, 2010)

AIM: To determine the effectiveness of postoperative concurrent daily low-dose cisplatin-based chemoradiation (CCRT) in patients with high-risk cervical cancer. PATIENTS AND METHODS: Patients with stage IB, IIA, or IIB cervical cancer who were initially treated with radical hysterectomy and pelvic lymphadenectomy, and were proven to have pelvic lymph node metastasis (pN1) or microscopic involvement of the parametrium (pT2b), participated in this study. Thirty-one patients received adjuvant CCRT with daily low-dose (6-8.5 mg/m(2)) cisplatin (daily CCRT group). A non-randomised control group of 44 patients received adjuvant radiotherapy alone (RT group). RESULTS: Overall survival (OS) at 4 years was 61% in the RT group and 91% in the daily CCRT group (p=0.004). Hazard ratio for poorer recurrence-free survival (RFS) in the RT group vs. the CCRT group was 7.9 (p=0.006). In the daily CCRT group, daily cisplatin chemotherapy was successfully completed in 27 out of 31 patients, although toxicity of grade >or=3 was found in 29% for neutropenia and 17% for gastrointestinal tract toxicity. CONCLUSION: Postoperative adjuvant CCRT with daily low-dose cisplatin improved RFS and OS of pT2b or pN1 patients, with acceptable compliance.

ゴナドトロピン放出ホルモン(Gn-RH)受容体変異は、ゴナドトロピン単独欠損症(IHH)の原因である。ミスセンス変異遺伝子のホモ接合や複合ヘテロ接合例が大部分を占めている。ヘテロ接合例では臨床症状を呈さない。変異受容体の発現実験から、変異の種類により受容体機能低下の程度が異なることが明らかにされている。受容体機能低下が強い変異をもつ患者では、臨床症状もより強い傾向がみられる。変異受容体は、立体構造の変化から合成後に細胞膜に運ばれることなく分解される、すなわち、フォールディング異常により機能低下をきたす。非ペプチド性Gn-RH受容体アンタゴニストにより変異受容体のフォールディングが助けられ、細胞膜への発現、リガンド結合能、シグナル伝達は部分的に回復することがわかってきた。(著者抄録)

Background: To report the cytologic characteristics of low grade endometrial stromal sarcoma with sex cord-like differtiation. Case: A 49 year-old woman presented with hypermenorrhea, menorrhalgia and anemia. With a diagnosis of degenerated leiomyoma of the uterus, simple total hysterectomy was conducted. Histologic examination revealed cells with ovoid to short, spindle-shaped nuclei resembling endometrial stromal cells proliferating in a space-occupying manner and compressing and partially infiltrating the myometrium. Some tumor cells were arranged in sex cord-like form, and hyalinization was observed in the center of the cord. Low grade endometrial stromal sarcoma with sex cord-like differentiation was diagnosed. Touch imprint cytologic examination of the tumor showed cells containing scanty cytoplasm and ovoid to spindle-shaped nuclei with little atypia they were scattered individually, aggregated in clusters, or arranged in cord glandular form. Hyaline-like substance was present in abundance. The histologic characteristics of the endometrial stromal sarcoma with sex cord-like differentiation were confirme by touch imprint cytology of the tumor. Conclusion: In this case of low grade endometrial stromal sarcoma with sex cord-like differentiation, cytologic examination revealed hyaline substance and tumor cells aligned in cord or glandular form. © The International Academy of Cytology.

前置癒着胎盤における帝王切開術は大量出血をきたす代表的な産科手術である。今回我々は、術中出血量の軽減を図ることを目的に、Intra-aortic balloon occlusion(IABO)を、前置胎盤の帝王切開術に使用しその有用性について検討した。対象は、最近1年半の間に当科で経験した、大量出血が予想された前置胎盤4症例である。腎動脈分岐部下の腹部大動脈でバルーンを拡張させ、術中最も出血量が増加すると思われるタイミングで1回につき最長20分間の血流遮断を行なった。偶発的にバルーンが虚脱した1例と比較して、他の3例の術中出血量は明らかに少なかった。IABOが前置癒着胎盤症例における周術期出血量低減に有用な手技となり得る可能性が示唆された。(著者抄録)

We describe a case of placental surface cyst. Intrauterine growth restriction or maternal floor infarction occurs in about 10% of cases [Brown DL, DiSalvo DN, Frates MC, et al. Placental surface cysts detected on sonography: histologic and clinical correlation. J Ultrasound Med. 2002 21(6):641-8]. Large or multiple cysts seem to have a higher frequency of these complications. To the best of our knowledge, there are a few reports about MR imaging of placental surface cysts. © 2009 Elsevier Ireland Ltd. All rights reserved.