Primary combined androgen blockade in localized disease and its mechanism

金沢大学医薬保健研究域医学系In spite of clinical practice guidelines such as NCI-PDQ - in which primary androgen deprivation therapy (PADT) is not recommended as the primary treatment for localized prostate cancer - many patients have been treated with PADT. One of the reasons is that urologists themselves permit patients\u27 desire because they know the effectiveness of PADT for some patients in their experiences. In this review we demonstrate basic mechanisms and the clinical efficacy of primary combined androgen blockade (PCAB) for localized or locally advanced prostate cancer. Then we discuss which patients are candidates for PCAB, and show that more than 30% of low- or intermediate-risk localized prostate cancers could be controlled in the long term with only PCAB. Short-term or intermittent PADT could not be recommended because of the possibilities of changing the character of the cancer cells by incomplete androgen ablation. We propose algorithms for the treatment of localized prostate cancer not only in low- and intermediate-risk groups but also in the high-risk group. © 2008

Androgen and prostate cancer: the role of primary androgen deprivation therapy in localized prostate cancer

金沢大学医薬保健研究域医学系Background: The basic mechanisms and clinical efficacy of primary androgen deprivation therapy (PADT), especially combined androgen blockade (CAB) for localized or locally advanced prostate cancer (PCa) have been outlined. An important point relates to which patients are suitable candidates for PADT. Methods: A retrospective review of the efficacy of PADT in 628 patients with localized or locally advanced PCa treated with PADT at seven institutions in Japan was carried out. Results: It was found that more than 30% of low- or intermediate-risk localized PCa patients could have their disease controlled over the long-term by PADT alone. Short-term or intermittent PADT could not be recommended because of the possibility of character change in the cancer cells as a result of incomplete androgen ablation. Conclusion: Algorithms are proposed for the treatment of localized PCa not only in low- and intermediate-risk groups, but also in the high-risk group. Future research directions are indicated. © 2008 WPMH GmbH

Gastrointestinal Stromal Tumor in a Patient with Neurofibromatosis: Abscess Formation in the Tumor Leading to Bacteremia and Seizure

A 66-year-old woman with neurofibromatosis type 1 (NF1) was brought to the emergency room with seizures and high-grade fever. Seizure in adult NF1 patients raises concern for intracranial lesions. However, neurological examination and central nervous system imaging failed to detect any causative intracranial lesions for her seizure. Gram-positive cocci, Streptococcus anginosus, were detected by blood cultures. Abdominal computed tomography revealed a well-defined round mass 7 cm in diameter, which was found to be a small intestinal gastrointestinal stromal tumor (GIST) containing an abscess. There was fistula formation between the intestinal lumen and the abscess, in which there were numerous Gram-positive cocci. The seizure may have been caused by hypoosmolality (hyponatremia and hypoproteinemia), which may result from decreased food intake associated with high-grade fever and general malaise. In this case GIST originating from the small intestine was invaded by S. anginosus through a fistula, leading to abscess formation, bacteremia, high-grade fever, and seizure, which was the first clinical manifestation

Evolution of Nanoscale Pore Structure in Coordination Polymers During Thermal and Chemical Exposure Revealed by Positron Annihilation

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71372/1/1598_ftp.pd

スタチンはYAP制御を介してゲムシタビンの肝内胆管癌抑制効果を増強させる

Cholangiocarcinoma (CCA) is associated with high mortality rates because of its resistance to conventional gemcitabine-based chemotherapy. Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reportedly exert anti-cancer effects in CCA and lower the risk of CCA; however, the underlying mechanism of these effects remains unclear. The proliferative and oncogenic activities of the transcriptional co-activator Yes-associated protein (YAP) are driven by its association with the TEA domain (TEAD) of transcription factors; thereby, upregulating genes that promote cell growth, inhibit apoptosis, and confer chemoresistance. This study investigated the effects of atorvastatin in combination with gemcitabine on the progression of human CCA associated with YAP oncogenic regulation. Both atorvastatin and gemcitabine concentration-dependently suppressed the proliferation of HuCCT-1 and KKU-M213 human CCA cells. Moreover, both agents induced cellular apoptosis by upregulating the pro-apoptotic marker BAX and downregulating the anti-apoptotic markers MCL1 and BCL2. Atorvastatin also significantly decreased the mRNA expression of the TEAD target genes CTGF, CYR61, ANKRD1, and MFAP5 in both CCA cell lines. A xenograft tumor growth assay indicated that atorvastatin and gemcitabine potently repressed human CCA cell-derived subcutaneous tumor growth by inhibiting YAP nuclear translocation and TEAD transcriptional activation. Notably, the anti-cancer effects of the individual agents were significantly enhanced in combination. These results indicate that gemcitabine plus atorvastatin could serve as a potential novel treatment option for CCA.博士（医学）・甲第778号・令和3年3月15日© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

Risedronate prevents persistent bone loss in prostate cancer patients treated with androgen deprivation therapy: Results of a 2-year follow-up study

Androgen deprivation therapy (ADT) for prostate cancer (PCa) causes bone loss. Although we reported previously that risedronate significantly recovers bone mineral density (BMD) for up to 12 months, there have been no reports with longer follow-up periods to date. This study extended our earlier series extending the follow-up period to 24 months. Eligible patients had histologically confirmed PCa without lumbar spine metastasis and underwent ADT. Lumbar spine BMD, urinary deoxypyridinoline (uDPD) and serum bone alkaline phosphatase were measured at 6, 12 and 24 months. Among the total of 96 patients, we analyzed 26 and 18 patients in risedronate administration and control groups, respectively. BMD relative to the young adult mean ratio, uDPD and serum bone alkaline phosphatase of the risedronate administration group recovered significantly after 24 months compared with the control group (P0.0001, P0.0001, and P0.0001, respectively). Transient blurred vision, malaise and vertigo were observed in 1 patient each among the 46 patients treated with risedronate within 28 days after first administration. Oral administration of risedronate is safe and effective for the recovery of ADT-induced bone loss in PCa patients even at 24 months after commencement of treatment. © 2011 Macmillan Publishers Limited All rights reserved

TGR5活性化はアナグリプチンによる糖尿病ラットに対する肝線維化抑制効果を増強する

Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from intestinal L cells, which maintains glycemic homeostasis. This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities. Collectively, TGR5 agonist and DPP-4 inhibitor appears to be a novel strategy against liver fibrosis under diabetic conditions.博士（医学）・甲第766号・令和3年3月15日© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

アンギオテンシン受容体を遮断することによりYes関連蛋白質の発癌活性が阻害されて胆管癌細胞増殖が抑制される

Cholangiocarcinoma (CCA) is a destructive malignancy with limited responsiveness to conventional chemotherapy. Although angiotensin receptor blockers (ARBs) have gained attention for their potential anticancer activity, little is known about their effects on CCA. The transcriptional co-activator, Yes-associated protein (YAP) is a critical oncogene in several cancers, including CCA. Following recent evidence showing that YAP is regulated by angiotensin II (AT-II), we investigated the effects of an ARB, losartan, on two human CCA cell lines (KKU-M213 and HuCCT-1) with regards to YAP oncogenic regulation. Losartan suppressed AT-II-induced CCA cell proliferation in a dose-dependent manner, induced apoptosis, decreased YAP (Ser127), and downregulated the YAP target genes CTGF, CYR61, ANKRD1, and MFAP5. However, losartan did not affect epithelial-mesenchymal transition, differentiation, or stemness in the CCA cells. Xenograft tumor growth assay showed that oral administration of a low clinical dose of losartan considerably reduced subcutaneous tumor burden and attenuated intratumor vascularization in CCA cell-derived xenograft tumors in BALB/c nude mice. These results indicate that ARB therapy could serve as a potential novel strategy for CCA treatment.博士（医学）・甲第728号・令和2年3月16日Copyright © 2018 Elsevier B.V. All rights reserved

胆汁酸吸着薬であるセベラマーは、内因性のリポポリサッカライドの過負荷を軽減して、非アルコール性脂肪性肝炎の肝線維化を改善する。

Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload.博士（医学）・甲第779号・令和3年3月15日© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

ラットを用いた非アルコール生脂肪肝炎におけるアンジオテンシンⅡ受容体拮抗薬とリファキシミン併用薬投与による肝線維化抑制効果の検討

The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut-liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-β and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis.博士（医学）・甲第780号・令和3年3月15日© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)