Publications by authors named "Yasuhiro Nakano"

76 Publications

Involvement of BMP-15 in glucocorticoid actions on ovarian steroidogenesis by rat granulosa cells.

Biochem Biophys Res Commun 2021 Apr 28;559:56-61. Epub 2021 Apr 28.

Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Electronic address:

To elucidate the impact of glucocorticoids on ovarian steroidogenesis and its molecular mechanism by focusing on bone morphogenetic proteins (BMPs), we examined the effect of dexamethasone (Dex) on estradiol and progesterone synthesis by using primary culture of rat granulosa cells. It was revealed that Dex treatment dose-dependently decreased estradiol production but increased progesterone production induced by follicle-stimulating hormone (FSH) by granulosa cells. In accordance with the effects of Dex on estradiol synthesis, Dex suppressed P450arom mRNA expression and cAMP synthesis induced by FSH. Dex treatment in turn enhanced basal as well as FSH-induced levels of mRNAs encoding the enzymes for progesterone synthesis including P450scc and 3βHSD but not StAR and 20αHSD. Of note, Dex treatment significantly upregulated transcription of the BMP target gene Id-1 and Smad1/5/9 phosphorylation in the presence of BMP-15 among the key ovarian BMP ligands. It was also found that Dex treatment increased the expression level of BMP type-I receptor ALK-6 among the type-I and -II receptors for BMP-15. Inhibitory Smad6/7 expression was not affected by Dex treatment. On the other hand, BMP-15 treatment upregulated glucocorticoid receptor (GR) expression in granulosa cells. Collectively, it was revealed that glucocorticoids elicit differential effects on ovarian steroidogenesis, in which GR and BMP-15 actions are mutually enhanced in granulosa cells.
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http://dx.doi.org/10.1016/j.bbrc.2021.04.085DOI Listing
April 2021

HIV-associated cerebral lymphoma in an elderly patient.

Geriatr Gerontol Int 2021 May 4;21(5):435-436. Epub 2021 Apr 4.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

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http://dx.doi.org/10.1111/ggi.14159DOI Listing
May 2021

Angina Simultaneously Diagnosed with the Recurrence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Diagnostics (Basel) 2021 Mar 6;11(3). Epub 2021 Mar 6.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) mainly affects young adults and can have a potential impact on social functioning. As this syndrome is associated with endothelial dysfunction, the heart can be damaged via ischemia due to endothelial damage. This might potentially lead to heart failure, which accounts for approximately 20% of deaths among patients with ME/CFS. While cardiac ischemia is thought be a pathophysiologically important manifestation of this syndrome, this is not yet reported. Herein, we present a case of a young female with newly diagnosed vasospastic or microvascular angina and concurrent exacerbation of ME/CFS severity. Her anginal symptoms, including exertional chest pain and transient chest discomfort, mimicked those of ME/CFS but were relieved after the administration of a calcium channel blocker. We emphasize the possibility of concurrent angina and exacerbation of ME/CFS and the importance of detecting cardiac ischemia to avoid unfavorable outcomes.
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http://dx.doi.org/10.3390/diagnostics11030460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001656PMC
March 2021

Simultaneous hot and cold thyroid nodules: Which is malignant?

Clin Case Rep 2021 Mar 26;9(3):1810-1811. Epub 2021 Jan 26.

Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.

Physicians should be aware of the risk of malignancy in patients with toxic multinodular goiter. Radionuclide scan cannot be used to predict the malignant potential of thyroid nodules. A comprehensive evaluation of imaging studies is needed.
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http://dx.doi.org/10.1002/ccr3.3843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981636PMC
March 2021

Gingival lesion leading to a diagnosis of angiosarcoma.

J Gen Fam Med 2021 Mar 1;22(2):90-91. Epub 2020 Nov 1.

Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.

A man who presented with a gingival tumor was finally diagnosed with angiosarcoma. It is important for primary care physicians to perform checkups of the oral cavity since oral lesions can lead to a diagnosis of serious systemic diseases.
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http://dx.doi.org/10.1002/jgf2.397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921341PMC
March 2021

Preclinical diagnosis and identification of the chimeric CYP11B1/CYP11B2 gene in two pediatric cases of a Japanese family with glucocorticoid-remediable aldosteronism.

Hypertens Res 2021 Mar 1. Epub 2021 Mar 1.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

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http://dx.doi.org/10.1038/s41440-021-00633-1DOI Listing
March 2021

Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers.

Cancer Chemother Pharmacol 2021 Jun 26;87(6):767-777. Epub 2021 Feb 26.

Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Purpose: The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (C) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer.

Methods: The C levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5.

Results: We analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the C values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 C levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 C values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035).

Conclusion: This study showed that the C of regorafenib was associated with bilirubin increase, and also clarified for the first time that the C of M5 was significantly correlated with hypertension and severe rash.
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http://dx.doi.org/10.1007/s00280-021-04237-xDOI Listing
June 2021

Comparison of Endothelial Dysfunction in Coronary Arteries with Bare Metal and 2-Generation Drug-Eluting Stents.

J Atheroscler Thromb 2021 Feb 19. Epub 2021 Feb 19.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University.

Aims: Previous studies suggested that implantation with a 1st-generation DES was associated with coronary endothelial dysfunction, which was associated with Rho-kinase activation. Second-generation drug-eluting stents (DESs) may preserve coronary endothelial function in stented coronary arteries; however, because of methodological limitations, further study is needed to clarify the association between 2-generation DESs and coronary endothelial dysfunction.

Methods: We retrospectively analysed the CuVIC trial database, where we identified 112 patients who underwent coronary stenting in the left coronary arteries with either a bare metal stent (BMS, n=53) or 2-generation DES (n=59). We compared vasomotions of target vessels with stents and non-target vessels without stents. Furthermore, we measured the Rho-kinase activation detected in mononucleocytes from aortic and coronary sinus blood.

Results: ACh-induced vasoconstrictive responses of target vessels were not enhanced with a 2-generation DES (45±21% vs. 44±20%, P=0.56, paired t-test), but significantly enhanced in the coronary arteries with a BMS (50±18% vs. 42±20%, P=0.002). Rho-kinase activation did not differ between patients with a BMS and 2-generation DES. In the target vessels with a BMS, large late lumen loss and acute coronary syndrome (ACS) at the index percutaneous coronary intervention (PCI) were associated with ACh-induced enhanced coronary vasoconstrictive responses.

Conclusions: Evaluation of ACh-induced vasomotion of target vessels comparing with non-target vessels revealed that 2-generation DESs were not associated with coronary endothelial dysfunction in target vessels, nor activation of Rho-kinase in the coronary sinus blood 6-8 months after stenting.
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http://dx.doi.org/10.5551/jat.61366DOI Listing
February 2021

Hypothalamic Mass Detected in Langerhans Cell Histiocytosis.

Intern Med 2020 Dec 29. Epub 2020 Dec 29.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.

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http://dx.doi.org/10.2169/internalmedicine.5946-20DOI Listing
December 2020

Acute encephalopathy associated with severe fever with thrombocytopaenia syndrome.

BMJ Case Rep 2020 Dec 28;13(12). Epub 2020 Dec 28.

Department of General Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan

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http://dx.doi.org/10.1136/bcr-2020-240075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772294PMC
December 2020

A rare complication: Infection in acromegalic renal cysts.

Clin Case Rep 2020 Dec 16;8(12):3551-3552. Epub 2020 Jul 16.

Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.

Renal cysts are detected in one third of acromegaly patients, especially in uncontrolled cases. Clinicians should pay attention to unexpected infection of enlarged renal cysts in acromegaly patients.
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http://dx.doi.org/10.1002/ccr3.3108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752462PMC
December 2020

Fate and functional roles of Prominin 1 cells in liver injury and cancer.

Sci Rep 2020 11 10;10(1):19412. Epub 2020 Nov 10.

Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Prominin 1 (PROM1) is one of a few clinically relevant progenitor markers in human alcoholic hepatitis (AH) and hepatocellular carcinoma (HCC), and mouse liver tumor initiating stem cell-like cells (TICs). However, the origin, fate and functions of PROM1 cells in AH and HCC are unknown. Here we show by genetic lineage tracing that PROM1 cells are derived in part from hepatocytes in AH and become tumor cells in mice with diethyl nitrosamine (DEN)-initiated, Western alcohol diet-promoted liver tumorigenesis. Our RNA sequencing analysis of mouse PROM1 cells, reveals transcriptomic landscapes indicative of their identities as ductular reaction progenitors (DRPs) and TICs. Indeed, single-cell RNA sequencing reveals two subpopulations of Prom1 Afp DRPs and Prom1 Afp TICs in the DEN-WAD model. Integrated bioinformatic analysis identifies Discodin Domain Receptor 1 (DDR1) as a uniquely upregulated and patient-relevant gene in PROM1 cells in AH and HCC. Translational relevance of DDR1 is supported by its marked elevation in HCC which is inversely associated with patient survival. Further, knockdown of Ddr1 suppresses the growth of TICs and TIC-derived tumor growth in mice. These results suggest the importance of PROM1 cells in the evolution of liver cancer and DDR1 as a potential driver of this process.
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http://dx.doi.org/10.1038/s41598-020-76458-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656457PMC
November 2020

Dysphagia Induced by Acromegalic Arthropathy.

Intern Med 2021 Apr 28;60(7):1127-1128. Epub 2020 Oct 28.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.

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http://dx.doi.org/10.2169/internalmedicine.5856-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079906PMC
April 2021

Involvement of clock gene expression, bone morphogenetic protein and activin in adrenocortical steroidogenesis by human H295R cells.

Endocr J 2021 Feb 6;68(2):243-250. Epub 2020 Oct 6.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

Functional interactions between the levels of clock gene expression and adrenal steroidogenesis were studied in human adrenocortical H295R cells. Fluctuations of Bmal1, Clock, Per2 and Cry1 mRNA levels were found in H295R cells treated with forskolin (FSK) in a serum-free condition. The changes of clock gene expression levels were diverged, with Clock mRNA level being significantly higher than Cry1 and Per2 mRNA levels after 12-h stimulation with FSK. After FSK induction, mRNA levels of StAR and CYP11B2 were highest at 12 hours and CYP17 mRNA level reached a peak at 6 hours, but HSD3B1 mRNA level was transiently decreased at 3 hours. The expression levels of Clock mRNA showed a significant positive correlation with StAR among the interrelationships between mRNA levels of key steroidogenic factors and clock genes. Knockdown of Clock gene by siRNA led to a significant reduction of FSK-induced expression of StAR and CYP17 after 12-h treatment with FSK. BMP-6 and activin, which modulate adrenal steroidogenesis, had inhibitory effects on Clock mRNA expression, whereas treatment with follistatin, a binding protein of activin, increased Clock mRNA levels in the presence of FSK, suggesting an endogenous function of activin in regulation of Clock mRNA expression. Collectively, the results indicated that changes of Clock mRNA expression, being upregulated by FSK and suppressed by BMP-6 and activin, were tightly linked to StAR expression by human adrenocortical cells.
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http://dx.doi.org/10.1507/endocrj.EJ20-0359DOI Listing
February 2021

Hepatic encephalopathy due to extrahepatic portosystemic shunt.

Clin Case Rep 2020 Sep 1;8(9):1852-1853. Epub 2020 Jun 1.

Department of General Medicine Dentistry and Pharmaceutical Sciences Okayama University Graduate School of Medicine Okayama Japan.

Clinicians should recognize extrahepatic portosystemic shunt as a cause of refractory or intermittent hepatic encephalopathy. Treatment strategies should be individualized according to patients' anatomic and hemodynamic status.
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http://dx.doi.org/10.1002/ccr3.2986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495749PMC
September 2020

Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16 Cells In Vivo.

Cell Metab 2020 11 18;32(5):814-828.e6. Epub 2020 Sep 18.

Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute of Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-0022, Japan.

Cell senescence plays a key role in age-associated organ dysfunction, but the in vivo pathogenesis is largely unclear. Here, we generated a p16-Cre-tdTomato mouse model to analyze the in vivo characteristics of p16 cells at a single-cell level. We found tdTomato-positive p16 cells detectable in all organs, which were enriched with age. We also found that these cells failed to proliferate and had half-lives ranging from 2.6 to 4.2 months, depending on the tissue examined. Single-cell transcriptomics in the liver and kidneys revealed that p16 cells were present in various cell types, though most dominant in hepatic endothelium and in renal proximal and distal tubule epithelia, and that these cells exhibited heterogeneous senescence-associated phenotypes. Further, elimination of p16 cells ameliorated nonalcoholic steatohepatitis-related hepatic lipidosis and immune cell infiltration. Our new mouse model and single-cell analysis provide a powerful resource to enable the discovery of previously unidentified senescence functions in vivo.
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http://dx.doi.org/10.1016/j.cmet.2020.09.006DOI Listing
November 2020

Aldosterone enhances progesterone biosynthesis regulated by bone morphogenetic protein in rat granulosa cells.

J Steroid Biochem Mol Biol 2020 10 21;203:105738. Epub 2020 Aug 21.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Electronic address:

Aldosterone (Aldo) is involved in various cardiovascular diseases such as hypertension and heart failure. Aldo levels are known to be increased in patients with polycystic ovary syndrome, and expression of the mineralocorticoid receptor (MR) has also been detected in the ovary. However, the effect of Aldo on reproductive function has yet to be elucidated. Here, we examined the effects of Aldo on follicular steroidogenesis using primary culture of rat granulosa cells by focusing on the ovarian bone morphogenetic protein (BMP) system acting as a luteinizing inhibitor. We found that Aldo treatment increased FSH-induced progesterone production in a concentration-responsive manner. Consistent with the effects on steroidogenesis, Aldo increased mRNA levels of progesterogenic factor and enzymes including StAR and P450scc, whereas Aldo failed to change FSH-induced estradiol and cAMP synthesis or P450arom expression by granulosa cells. Progesterone production and StAR expression induced by FSH and Aldo were reversed by co-treatment with spironolactone, suggesting the involvement of geonomic MR action. Aldo treatment attenuated Smad1/5/9 phosphorylation and Id1 transcription induced by BMP-6. Furthermore, Aldo enhanced the expression of inhibitory Smad6 in the presence of BMP-6. In addition, BMP-6 downregulated MR expression, while Aldo modulated the mRNA levels of endogenous BMP-6 and BMP type-II receptors, indicating the existence of a feedback loop between the BMP system and MR in granulosa cells.  Collectively, the results indicated that Aldo predominantly enhances FSH-induced progesterone production by inhibiting BMP-Smad signaling, suggesting a novel role of Aldo in ovarian steroidogenesis and a functional link between MR and BMP pathways in granulosa cells.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105738DOI Listing
October 2020

Visualization and isolation of zone-specific murine hepatocytes that maintain distinct cytochrome P450 oxidase expression in primary culture.

Biochem Biophys Res Commun 2020 07 3;528(3):420-425. Epub 2020 Jun 3.

Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan; Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Japan; Institute of Medical Sciences, Tokai University, Isehara, Japan. Electronic address:

Parenchymal hepatocytes are responsible for most of the metabolic functions of the liver, but exhibit distinct functional properties depending on their localization within the hepatic lobule. Cytochrome P450 oxidases represent a family of drug-metabolizing enzymes, which are expressed predominantly in hepatocytes localized in the centrilobular area (zone 3). The present study describes a unique transgenic mouse strain that distinguishes zone 3 hepatocytes from periportal zone 1 hepatocytes by the intensity of EGFP fluorescence. Both zone 1 and zone 3 hepatocytes isolated from these mice showed the same zone-specific gene expression patterns as in liver tissue in vivo. Experiments using primary cultures of hepatocytes indicated that a combination of low oxygen concentration and activation of Wnt/β-catenin signaling maintained the expression of zone 3-specific P450 drug-metabolizing enzymes, which was characterized by their susceptibility to acetaminophen-induced mitochondrial dysfunction. These zone-specific hepatocytes provide a useful system in the research area of liver pathophysiology and drug development.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.202DOI Listing
July 2020

Multidimensional imaging of liver injury repair in mice reveals fundamental role of the ductular reaction.

Commun Biol 2020 06 5;3(1):289. Epub 2020 Jun 5.

Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.

Upon severe and/or chronic liver injury, ectopic emergence and expansion of atypical biliary epithelial-like cells in the liver parenchyma, known as the ductular reaction, is typically induced and implicated in organ regeneration. Although this phenomenon has long been postulated to represent activation of facultative liver stem/progenitor cells that give rise to new hepatocytes, recent lineage-tracing analyses have challenged this notion, thereby leaving the pro-regenerative role of the ductular reaction enigmatic. Here, we show that the expanded and remodelled intrahepatic biliary epithelia in the ductular reaction constituted functional and complementary bile-excreting conduit systems in injured parenchyma where hepatocyte bile canalicular networks were lost. The canalicular collapse was an incipient defect commonly associated with hepatocyte injury irrespective of cholestatic statuses, and could sufficiently provoke the ductular reaction when artificially induced. We propose a unifying model for the induction of the ductular reaction, where compensatory biliary epithelial tissue remodeling ensures bile-excreting network homeostasis.
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http://dx.doi.org/10.1038/s42003-020-1006-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275065PMC
June 2020

Multiple Deep-seated Dentofacial Abscesses Caused by Multidrug-resistant Viridans Group Streptococci.

Intern Med 2020 Aug 8;59(16):2067-2070. Epub 2020 May 8.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.

Odontogenic infections, generally caused by dental caries and periodontal disease, can result in fatal illness. We herein report a 71-year-old Japanese woman with type 2 diabetes and hemodialysis who suffered from multiple dentofacial abscesses mainly caused by multidrug-resistant Streptococcus oralis. She complained of pain and swelling of her face, with an extraoral fistula from the left cheek. Following 3 surgical debridement procedures and partial mandibulectomy, in addition to 12 weeks of antimicrobial therapy, the multiple dentofacial abscesses were ameliorated. A combination of surgical and antimicrobial treatments following an early diagnosis is essential for reducing further complications.
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http://dx.doi.org/10.2169/internalmedicine.4283-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492120PMC
August 2020

Coronary Spastic Angina Induced by Adrenal Insufficiency.

Intern Med 2020 Aug 30;59(15):1873-1877. Epub 2020 Apr 30.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.

Adrenal insufficiency patients are treated with glucocorticoid replacement therapy. However, mimicking the in vivo circadian rhythm of cortisol levels is challenging, and suboptimal replacement increases the risk of mortality from cardiovascular disease. We herein report a case of coronary spastic angina (CSA) with simultaneous low early-morning serum cortisol levels in a patient undergoing corticosteroid replacement therapy for primary adrenal insufficiency. Steroid therapy is reportedly effective for refractory angina, but underlying adrenal deficiency has never been revealed. Our case intimates the probable risk of CSA as a complication of relative adrenal insufficiency and highlights the effectiveness of dexamethasone in these patients.
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http://dx.doi.org/10.2169/internalmedicine.4337-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474991PMC
August 2020

A Novel Composite Biomaterial Made of Jellyfish and Porcine Collagens Accelerates Dermal Wound Healing by Enhancing Reepithelization and Granulation Tissue Formation in Mice.

Adv Wound Care (New Rochelle) 2020 06 2;9(6):295-311. Epub 2019 Oct 2.

Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.

Impaired dermal wound healing represents a major medical issue in today's aging populations. Granulation tissue formation in the dermis and reepithelization of the epidermis are both important and necessary for proper wound healing. Although a number of artificial dermal grafts have been used to treat full-thickness dermal loss in humans, they do not induce reepithelization of the wound, requiring subsequent epithelial transplantation. In the present study, we sought a novel biomaterial that accelerates the wound healing process. We prepared a composite biomaterial made of jellyfish and porcine collagens and developed a hybrid-type dermal graft that composed of the upper layer film and the lower layer sponge made of this composite biomaterial. Its effect on dermal wound healing was examined using a full-thickness excisional wound model. Structural properties of the dermal graft and histological features of the regenerating skin tissue were characterized by electron microscopic observation and immunohistological examination, respectively. The composite biomaterial film stimulated migration of keratinocytes, leading to prompt reepithelization. The regenerating epithelium consisted of two distinct cell populations: keratin 5-positive basal keratinocytes and more differentiated cells expressing tight junction proteins such as claudin-1 and occludin. At the same time, the sponge made of the composite biomaterial possessed a significantly enlarged intrinsic space and enhanced infiltration of inflammatory cells and fibroblasts, accelerating granulation tissue formation. This newly developed composite biomaterial may serve as a dermal graft that accelerates wound healing in various pathological conditions. We have developed a novel dermal graft composed of jellyfish and porcine collagens that remarkably accelerates the wound healing process.
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http://dx.doi.org/10.1089/wound.2019.1014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155930PMC
June 2020

A rare case of oncocytic adrenocortical carcinoma clinically presented as an incidentaloma.

Endocr J 2020 Aug 4;67(8):883-888. Epub 2020 May 4.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

Adrenocortical carcinoma (ACC) is a rare aggressive tumor originating from adrenocortical parenchymal cells and its incidence is approximately 1 per million population per year. An oncocytic ACC is a recently identified entity among the several known histopathological variants of ACC, which is characterized by oncocytic cells, and only a few cases in the available literature have reported this tumor. In contrast to conventional ACCs, oncocytic ACCs usually manifest as solitary lesions presenting in adults without any sex predilection. We report a case of a 70-year-old Japanese man who presented with an incidentally discovered retroperitoneal mass without any evidence of excessive corticosteroid secretion. Laboratory and imaging studies, as well as transgastric endoscopic ultrasound-guided fine needle aspiration failed to establish a definitive diagnosis. Thus, the patient underwent surgical resection of the left-sided peritoneal tumor. Weiss score was positive in 6/9 points and the tumor met two major criteria of the Lin-Weiss-Bisceglia (LWB) system leading to a diagnosis of an oncocytic variant of ACC. Based on our findings in this patient, we conclude that a combination of the Weiss and LWB criteria is required to determine the malignant potential of oncocytic adrenal tumors because ACCs and oncocytomas could be frequently indistinguishable. Careful histopathological examination is pivotal in confirming the oncocytic component in the lesion and hence definitive diagnosis of ACCs.
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http://dx.doi.org/10.1507/endocrj.EJ20-0024DOI Listing
August 2020

Reversible expansion of pancreatic islet progenitors derived from human induced pluripotent stem cells.

Genes Cells 2020 May 6;25(5):302-311. Epub 2020 Mar 6.

Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.

Transplantation of pancreatic islets is an effective therapy for severe type 1 diabetes. As donor shortage is a major problem for this therapy, attempts have been made to produce a large number of pancreatic islets from human pluripotent stem cells (hPSCs). However, as the differentiation of hPSCs to pancreatic islets requires multiple and lengthy processes using various expensive cytokines, the process is variable, low efficiency and costly. Therefore, it would be beneficial if islet progenitors could be expanded. Neurogenin3 (NGN3)-expressing pancreatic endocrine progenitor (EP) cells derived from hPSCs exhibited the ability to differentiate into pancreatic islets while their cell cycle was arrested. By using a lentivirus vector, we introduced several growth-promoting genes into NGN3-expressing EP cells. We found that SV40LT expression induced proliferation of the EP cells but reduced the expression of endocrine lineage-commitment factors, NGN3, NEUROD1 and NKX2.2, resulting in the suppression of islet differentiation. By using the Cre-loxP system, we removed SV40LT after the expansion, leading to re-expression of endocrine-lineage commitment genes and differentiation into functional pancreatic islets. Thus, our findings will pave a way to generate a large quantity of functional pancreatic islets through the expansion of EP cells from hPSCs.
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http://dx.doi.org/10.1111/gtc.12759DOI Listing
May 2020

X-linked Hypophosphatemia (XLH) Mimicking Rheumatic Disease.

Intern Med 2020 05 17;59(9):1233-1234. Epub 2020 Jan 17.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.

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http://dx.doi.org/10.2169/internalmedicine.4029-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270752PMC
May 2020

Malignant Lymphoma Developed in the Hypothalamus.

Intern Med 2020 04 26;59(7):1009-1010. Epub 2019 Dec 26.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.

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http://dx.doi.org/10.2169/internalmedicine.3655-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184080PMC
April 2020

[Effects of Seven Tyrosine Kinase Inhibitors on the Anticoagulation Activity of Warfarin].

Gan To Kagaku Ryoho 2019 Nov;46(11):1733-1739

Dept. of Pharmacy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research.

Several studies have reported increased anticoagulation effect of warfarin(WF)when combined with tyrosine kinase inhibitors(TKIs), such as gefitinib and erlotinib. However, effects of TKIs other than gefitinib and erlotinib on the anticoagulation effect of WF have not been clarified. To assess the degree and onset of prothrombin time-international normalized ratio (PT-INR)elevation and changes in WF daily doses in patients additionally receiving TKIs, this retrospective, single-center observational study compared PT-INR values and WF daily doses during WF treatment in the absence and presence of TKIs. Seven different TKIs(afatinib, alectinib, axitinib, crizotinib, pazopanib, regorafenib, and vandetanib)were prescribed during treatment with WF of venous thromboembolism in 10 cancer patients. Compared to baseline PT-INR, significant PT-INR elevations were observed in all patients during the combination therapy. The median PT-INR increased 1.6-fold from the baseline in the presence of TKIs(p<0.01), and the onset of PT-INR elevation was observed at a median of 18 days. As all patients receiving WF with the 7 TKIs showed PT-INR elevation, enhancement of the anticoagulation effect of WF in the presence of TKIs appears to be highly frequent. PT-INR should be carefully monitored, and adjusting the WF dosage may become necessary during the WF and TKI combination therapy.
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November 2019

A Deactivation Factor of Fibrogenic Hepatic Stellate Cells Induces Regression of Liver Fibrosis in Mice.

Hepatology 2020 04 6;71(4):1437-1452. Epub 2020 Mar 6.

Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.

Background And Aims: Hepatic stellate cells (HSCs), a key player in the progression of liver fibrosis, are activated by various inflammatory stimuli and converted to myofibroblast-like cells with excessive collagen production. Despite many attempts to suppress activation of HSCs or inhibit collagen production in activated HSCs, their clinical applications have not been established yet. Recently, the deactivation of HSCs has been reported as a mechanism underlying the reversibility of experimental liver fibrosis. In the present study, we sought for deactivation factors of HSCs that induce regression of established liver fibrosis.

Approach And Results: We identified transcription factor 21 (Tcf21) as one of the transcription factors whose expression was up-regulated in parallel to the differentiation of fetal HSCs. Expression of Tcf21 in HSCs remarkably decreased during culture-induced activation in vitro and in murine and human fibrotic liver tissue in vivo. This reduced Tcf21 expression was recovered during the spontaneous regression of murine liver fibrosis. Tcf21 was also examined for its effects by adeno-associated virus serotype 6-mediated Tcf21 gene transfer into cultured activated HSCs and mice with carbon tetrachloride- or methionine-choline deficient diet-induced liver fibrosis. Overexpression of Tcf21 in activated HSCs not only suppressed fibrogenic gene expression but also restored cells, at least in part, to a quiescent phenotype both in vitro and in vivo. These phenotypic changes of HSCs were accompanied by the regression of steatohepatitis and fibrosis and improved hepatic architecture and function.

Conclusions: Tcf21 has been identified as a deactivation factor of fibrogenic HSCs, providing insight into a treatment strategy for the otherwise intractable liver fibrosis.
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http://dx.doi.org/10.1002/hep.30965DOI Listing
April 2020

[Effects of Tyrosine Kinase Inhibitors on Control of PT-INR in Patients Receiving Warfarin].

Gan To Kagaku Ryoho 2019 Sep;46(9):1413-1419

Dept. of Pharmacy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research.

Few studies have evaluated the influence of anticancer drugs on the anticoagulation response to warfarin(WF). This retrospective, single-center, observationalstudy evaluated the changes in prothrombin time-internationalnormal ized ratio (PT-INR)in patients receiving a combination of WF and anticancer drugs. We compared(a)PT-INR changes between groups receiving WF and concomitantly started on either tyrosine kinase inhibitors(TKI)(WF+TKI group: n=14)or anticancer drugs other than TKI(WF+non-TKI group: n=20)and(b)PT-INR changes between groups that were started on WF concomitantly while receiving either TKI(TKI+WF group: n=16)or anticancer drugs other than TKI(non-TKI+WF group: n=13). (a)PT-INR changes were significantly larger in the WF+TKI group than in the WF+non-TKI group(2.23 vs 0.42, p<0.001). In the WF+TKI group, the WF dose was reduced after all 14 patients(100.0%)showed increased PT-INR.(b)PT-INR changes during the WF induction period were significantly larger in the TKI+WF group than in the non-TKI+WF group(2.18 vs 0.68, p<0.001). In the TKI+WF group, the WF dose was reduced after 12 patients(75.0%)showed increased PT-INR. It might be necessary to consider a reduction in WF dose when WF is administered in combination with TKIs.
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September 2019

Identification of risk factors for venous thromboembolism and evaluation of Khorana venous thromboembolism risk assessment in Japanese lung cancer patients.

J Cardiol 2020 01 12;75(1):110-114. Epub 2019 Aug 12.

Department of Pharmacy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: The reported incidence of venous thromboembolism (VTE) in cancer patients is 4-20%. The Khorana VTE risk score (KRS) and the Vienna VTE risk score (VRS) have been proposed as scoring models for evaluation of cancer-associated VTE. However, the risk factors of VTE in Japanese lung cancer patients have not been clarified.

Methods: This retrospective study included 682 hospitalized Japanese patients with newly diagnosed lung cancer who were examined for VTE on admission between January 2014 and December 2016.

Results: Seventy-one (10.4%) of the 682 patients were diagnosed with VTE. Multivariate logistic regression analysis showed that body mass index (BMI) ≥25 kg/m (OR, 2.02; 95% CI, 1.06-3.72), white blood cell (WBC) count >11 × 10/L (OR, 2.31; 95% CI, 1.11-4.61), pre-chemotherapy serum D-dimer concentration ≥1.44 μg/mL (OR, 2.73; 95% CI, 1.49-4.99), and non-small cell lung cancer (OR, 3.13; 95% CI, 1.32-9.23) were significantly associated with VTE in these patients. The cut-off values for BMI, WBC count, and D-dimer concentration determined using receiver operating characteristic curves were 25.4 kg/m, 11.2 × 10/L, and 1.95 µg/mL, respectively.

Conclusions: In this study, we were able to identify four independent risk factors for cancer-associated VTE in Japanese lung cancer patients for the first time. Moreover, we showed that a cut-off level of ≥25 kg/m for BMI was a risk factor for VTE in this cohort.
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http://dx.doi.org/10.1016/j.jjcc.2019.06.013DOI Listing
January 2020