Publications by authors named "Tomoaki Tanaka"

181 Publications

Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis.

Leukemia 2021 Sep 8. Epub 2021 Sep 8.

Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Insufficiency of polycomb repressive complex 2 (PRC2), which trimethylates histone H3 at lysine 27, is frequently found in primary myelofibrosis and promotes the development of JAK2V617F-induced myelofibrosis in mice by enhancing the production of dysplastic megakaryocytes. Polycomb group ring finger protein 1 (Pcgf1) is a component of PRC1.1, a non-canonical PRC1 that monoubiquitylates H2A at lysine 119 (H2AK119ub1). We herein investigated the impact of PRC1.1 insufficiency on myelofibrosis. The deletion of Pcgf1 in JAK2V617F mice strongly promoted the development of lethal myelofibrosis accompanied by a block in erythroid differentiation. Transcriptome and chromatin immunoprecipitation sequence analyses showed the de-repression of PRC1.1 target genes in Pcgf1-deficient JAK2V617F hematopoietic progenitors and revealed Hoxa cluster genes as direct targets. The deletion of Pcgf1 in JAK2V617F hematopoietic stem and progenitor cells (HSPCs), as well as the overexpression of Hoxa9, restored the attenuated proliferation of JAK2V617F progenitors. The overexpression of Hoxa9 also enhanced JAK2V617F-mediated myelofibrosis. The expression of PRC2 target genes identified in PRC2-insufficient JAK2V617F HSPCs was not largely altered in Pcgf1-deleted JAK2V617F HSPCs. The present results revealed a tumor suppressor function for PRC1.1 in myelofibrosis and suggest that PRC1.1 insufficiency has a different impact from that of PRC2 insufficiency on the pathogenesis of myelofibrosis.
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http://dx.doi.org/10.1038/s41375-021-01402-2DOI Listing
September 2021

Epigenetic modifications underlie the differential adipogenic potential of preadipocytes derived from human subcutaneous fat tissue.

Am J Physiol Cell Physiol 2021 09 28;321(3):C596-C606. Epub 2021 Jul 28.

Department of Plastic Surgery, Chiba University, Chiba-city, Chiba, Japan.

Ceiling culture-derived preadipocytes (ccdPAs) and adipose-derived stem cells (ASCs) can be harvested from human subcutaneous fat tissue using the specific gravity method. Both cell types possess a similar spindle shape without lipid droplets. We previously reported that ccdPAs have a higher adipogenic potential than ASCs, even after a 7-wk culture. We performed a genome-wide epigenetic analysis to examine the mechanisms contributing to the adipogenic potential differences between ccdPAs and ASCs. Methylation analysis of cytosines followed by guanine (CpG) using a 450-K BeadChip was performed on human ccdPAs and ASCs isolated from three metabolically healthy females. Chromatin immunoprecipitation sequencing was performed to evaluate trimethylation at lysine 4 of histone 3 (H3K4me3). Unsupervised machine learning using t-distributed stochastic neighbor embedding to interpret 450,000-dimensional methylation assay data showed that the cells were divided into ASC and ccdPA groups. In Kyoto Encyclopedia of Genes and Genomes pathway analysis of 1,543 genes with differential promoter CpG methylation, the peroxisome proliferator-activated receptor (PPAR) and adipocytokine signaling pathways ranked in the top 10 pathways. In the PPARγ gene, H3K4me3 peak levels were higher in ccdPAs than in ASCs, whereas promoter CpG methylation levels were significantly lower in ccdPAs than in ASCs. Similar differences in promoter CpG methylation were also seen in the fatty acid-binding protein 4 and leptin genes. In conclusion, we analyzed the epigenetic status of adipogenesis-related genes as a potential mechanism underlying the differences in adipogenic differentiation capability between ASCs and ccdPAs.
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http://dx.doi.org/10.1152/ajpcell.00387.2020DOI Listing
September 2021

ICAM1-Negative Intravascular Large B-Cell Lymphoma of the Pituitary Gland: A Case Report and Literature Review.

AACE Clin Case Rep 2021 Jul-Aug;7(4):249-255. Epub 2021 Feb 9.

Department of Endocrinology, Hematology and Gerontology, Chiba University Hospital, Chiba, Japan.

Objective: Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive type of B-cell lymphoma with large cells growing within the lumen of blood vessels. Although previous reports revealed highly variable symptoms resulting from small-vessel occlusion by neoplastic cells in a variety of organs, there are few reports of IVLBCL with pituitary involvement.

Method: We present a case of IVLBCL with pituitary infiltration from our institution together with a literature review of similar cases to better understand this rare case of IVLBCL involving the pituitary gland.

Results: Our case and the pertinent literature demonstrated that IVLBCL with pituitary involvement predominantly occurred in women at a mean age of 64 years, and most of them showed panhypopituitarism that was reversible after standard therapy of rituximab-containing chemotherapy with intrathecal methotrexate. Notably, the pituitary biopsy in our case revealed that atypical large B-cells found within blood vessels and the pituitary gland were negative for intercellular adhesion molecule 1. Intercellular adhesion molecule 1-negative lymphoid cells may have contributed to panhypopituitarism by extravasation into the pituitary tissues, which do not have a blood-brain barrier and receive abundant blood flow.

Conclusion: IVLBCL of the pituitary gland is a rare lymphoma with nonspecific manifestations and a dismal prognosis. Recognition of the clinicopathological features is necessary for early clinical diagnosis and appropriate treatment.
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http://dx.doi.org/10.1016/j.aace.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282537PMC
February 2021

Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro-T cells.

J Exp Med 2021 Aug 28;218(8). Epub 2021 Jun 28.

Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA.

PU.1 (encoded by Spi1), an ETS-family transcription factor with many hematopoietic roles, is highly expressed in the earliest intrathymic T cell progenitors but must be down-regulated during T lineage commitment. The transcription factors Runx1 and GATA3 have been implicated in this Spi1 repression, but the basis of the timing was unknown. We show that increasing Runx1 and/or GATA3 down-regulates Spi1 expression in pro-T cells, while deletion of these factors after Spi1 down-regulation reactivates its expression. Leveraging the stage specificities of repression and transcription factor binding revealed an unconventional but functional site in Spi1 intron 2. Acute Cas9-mediated deletion or disruption of the Runx and GATA motifs in this element reactivates silenced Spi1 expression in a pro-T cell line, substantially more than disruption of other candidate elements, and counteracts the repression of Spi1 in primary pro-T cells during commitment. Thus, Runx1 and GATA3 work stage specifically through an intronic silencing element in mouse Spi1 to control strength and maintenance of Spi1 repression during T lineage commitment.
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http://dx.doi.org/10.1084/jem.20202648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241539PMC
August 2021

Vitamin K-Dependent γ-Glutamyl Carboxylase in Sertoli Cells Is Essential for Male Fertility in Mice.

Mol Cell Biol 2021 03 24;41(4). Epub 2021 Mar 24.

Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan

γ-Glutamyl carboxylase (GGCX) is a vitamin K (VK)-dependent enzyme that catalyzes the γ-carboxylation of glutamic acid residues in VK-dependent proteins. The anticoagulant warfarin is known to reduce GGCX activity by inhibiting the VK cycle and was recently shown to disrupt spermatogenesis. To explore GGCX function in the testis, here, we generated Sertoli cell-specific conditional knockout ( scKO) mice and investigated their testicular phenotype. scKO mice exhibited late-onset male infertility. They possessed morphologically abnormal seminiferous tubules containing multinucleated and apoptotic germ cells, and their sperm concentration and motility were substantially reduced. The localization of connexin 43 (Cx43), a gap junction protein abundantly expressed in Sertoli cells and required for spermatogenesis, was distorted in scKO testes, and Cx43 overexpression in Sertoli cells rescued the infertility of scKO mice. These results highlight GGCX activity within Sertoli cells, which promotes spermatogenesis by regulating the intercellular connection between Sertoli cells and germ cells.
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http://dx.doi.org/10.1128/MCB.00404-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088131PMC
March 2021

TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia.

Oncogene 2021 02 8;40(7):1217-1230. Epub 2021 Jan 8.

Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.

TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in various AML cell lines. TAS4464 treatments resulted in the activation of both the caspase-9-mediated intrinsic apoptotic pathway and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined treatment with inhibitors of these caspases markedly diminished TAS4464-induced apoptosis. In each apoptotic pathway, TAS4464 induced the mRNA transcription of the intrinsic proapoptotic factor NOXA and decreased that of the extrinsic antiapoptotic factor c-FLIP. RNA-sequencing analysis showed that the signaling pathway of the CRL substrate c-Myc was enriched after TAS4464 treatment. Chromatin immunoprecipitation (ChIP) assay revealed that TAS4464-induced c-Myc bound to the PMAIP1 (encoding NOXA) and CFLAR (encoding c-FLIP) promoter regions, and siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.
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http://dx.doi.org/10.1038/s41388-020-01586-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892340PMC
February 2021

Association of urinary free cortisol with bone formation in patients with mild autonomous cortisol secretion.

Clin Endocrinol (Oxf) 2021 04 17;94(4):544-550. Epub 2020 Dec 17.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Context: Mild autonomous cortisol secretion (ACS) is associated with an increased risk of vertebral fractures (VFx). However, the influence of this condition on bone turnover or its association with mild ACS is still controversial.

Objective: This study aimed to evaluate the impact of mild ACS on bone quality among patients living with the disease.

Design And Setting: A retrospective study was conducted using data from 55 mild ACS and 12 nonfunctioning adrenal tumour (NFT) patients who visited Chiba University Hospital, Japan, from 2006 to 2018.

Patients And Main Outcome Measures: We analysed clinical features and bone-related factors, including bone mineral density (BMD) and VFx, performed blood tests to assess bone metabolism markers in patients with mild ACS and NFT, and assessed the associations between bone-related markers and endocrinological parameters in patients with mild ACS.

Results: No significant differences between mild ACS and NFT patients were observed with respect to the presence or absence of VFx and BMD. Urinary free cortisol (UFC) was higher in mild ACS patients with VFx than those without (p = .037). The T-score and young adult mean (YAM) of the BMD of the femoral neck in mild ACS patients with a body mass index <25 were positively correlated with dehydroepiandrosterone sulphate levels (ρ: 0.42, p = .017; ρ: 0.40, p = .024, respectively). Pearson's correlation analysis showed that bone-specific alkaline phosphatase was negatively correlated with UFC in the patients with mild ACS (ρ: -0.37, p = .026).

Conclusions: These results suggest that urinary free cortisol may be useful for predicting bone formation in mild ACS patients.
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http://dx.doi.org/10.1111/cen.14385DOI Listing
April 2021

Comparison of post-implant dosimetrics between intraoperatively built custom-linked seeds and loose seeds by sector analysis at 24 hours and 1 month for localized prostate cancer.

J Contemp Brachytherapy 2020 Aug 21;12(4):317-326. Epub 2020 Aug 21.

Department of Diagnostic and Interventional Radiology/Radiation Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Purpose: To compare post-implant dosimetrics between intraoperatively built custom-linked (IBCL) seeds and loose seeds (LS) at 24 hours and 1 month by sector analysis, and to evaluate the effect of IBCL seeds with regard to change in dosimetric parameters, in patients with prostate cancer treated with brachytherapy.

Material And Methods: Consecutive patients treated for localized prostate cancer who received definitive brachytherapy between March 2013 and October 2017 were retrospectively analyzed. Prostate V (PV), prostate D (PD), prostate V (PV), urethral D (UD), urethral V (UV), and rectal V (RV) were assessed.

Results: Thirty-two patients were treated with LS and 32 patients were treated with IBCL seeds. The median follow-up time was 49.9 months in the LS group and 27.1 months in the IBCL group. PV, UV, and UD at 24 hours and UD at 1 month showed significant difference (-test), and standard deviation (SD) tended to be lower in the IBCL group. Analysis of change in the variables revealed significance for ΔPV and ΔPD (-test, = 0.014 and < 0.001, respectively), and ΔPV and ΔUD showed marginal significance ( = 0.084 and 0.097, respectively). PV, UV, and UD at 24 hours and 1 month were significantly lower in the IBCL group, and there was no significant difference in PV, PD, and RV compared with the LS group (-test). The homogeneity index (HI) was significantly higher in the IBCL group ( < 0.001).

Conclusions: In this retrospective single institutional study, there was a decrease in the SD of the dosimetric parameters in the IBCL group, and it was statistically significant in change in the variables between 24 hours and 1 month (-test). The use of IBCL seeds significantly decreased PV, UV, and UD, and significantly improved HI, without lowering PD or PD.
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http://dx.doi.org/10.5114/jcb.2020.98110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690227PMC
August 2020

Adrenalectomy in Japanese patients with subclinical Cushing syndrome: 1-mg dexamethasone suppression test to predict the surgical benefit.

Int J Urol 2021 03 30;28(3):273-279. Epub 2020 Nov 30.

Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.

Objectives: To investigate whether the result of the 1-mg dexamethasone suppression test can predict the improvement of comorbidities after adrenalectomy in patients with subclinical Cushing syndrome.

Methods: This retrospective study included 117 subclinical Cushing syndrome patients who underwent adrenalectomy. The numbers of prescribed drugs for metabolic comorbidities and the clinical variables at diagnosis were compared with those at the follow up. Patients were classified into subgroups according to the result of the 1-mg dexamethasone suppression test.

Results: Significant improvements in blood pressure, serum cholesterol and body mass index were observed. Furthermore, a significant improvement in glycated hemoglobin was observed in patients with diabetes mellitus. These improvements led to a discontinuation or reduction of prescribed drugs after surgery. In addition, the greatest reduction of prescribed drugs was observed in patients whose serum cortisol levels were between 1.8 and 3.0 µg/dL after the 1-mg dexamethasone suppression test.

Conclusions: The result of the 1-mg dexamethasone suppression test can be a useful factor predicting the improvement of comorbidities after adrenalectomy. Current data might give us a new insight into the decision-making for the treatment of subclinical Cushing syndrome.
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http://dx.doi.org/10.1111/iju.14445DOI Listing
March 2021

Two cases of symptomatic secondary hypophysitis due to Rathke's cleft cysts treated with glucocorticoids: long-term follow-up.

Endocr J 2021 Mar 21;68(3):269-279. Epub 2020 Oct 21.

Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.

Rathke's cleft cyst (RCC) is a common incidental tumor in the hypothalamic-pituitary region. Some reports have shown that the clinical symptoms and endocrine functions of symptomatic RCCs are temporarily improved by glucocorticoid administration. However, it is still unknown whether glucocorticoid treatment is effective for symptomatic RCCs according to long-term observations. In this study, we describe the long-term clinical outcomes of two cases of glucocorticoid-treated biopsy-proven secondary hypophysitis caused by RCCs. We summarize the symptoms, imaging findings, and endocrine evaluations of two symptomatic RCC patients with concomitant hypophysitis before and after prednisolone treatment. In both evaluated cases, visual impairments and altered endocrine parameters were present due to chiasm and stalk compression; these outcomes improved after shrinkage of RCCs in response to prednisolone administration, and partial recovery of anterior pituitary hormone secretion was observed. However, in both cases, the deficits in anterior pituitary hormone secretion recurred, possibly due to persistent inflammatory infiltration in the RCCs and pituitary glands. After relapse of hypophysitis, anterior hormone secretion did not fully recover. In our cases of secondary hypophysitis caused by RCCs, prednisolone administration had an early effect of cyst shrinkage, followed by partial improvements in clinical symptoms and pituitary functions. However, long-term observation showed that prednisolone treatment did not contribute to complete improvement in anterior pituitary hormone dysfunction.
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http://dx.doi.org/10.1507/endocrj.EJ20-0361DOI Listing
March 2021

131I-6β-iodomethyl-19-norcholesterol adrenal scintigraphy as an alternative to adrenal venous sampling in differentiating aldosterone-producing adenoma from bilateral idiopathic hyperaldosteronism.

Nucl Med Commun 2020 Dec;41(12):1226-1233

Departments of Diagnostic Radiology and Radiation Oncology.

Objective: To assess the correlation value between adrenal venous sampling (AVS) and I-6β-iodomethyl-19-norcholesterol (NP-59) adrenal scintigraphy in differentiating aldosterone-producing adenoma (APA) from bilateral idiopathic hyperaldosteronism (BHA), and the use of NP-59 scintigraphy as an alternative to AVS.

Methods: Overall, 29 patients with APA or BHA who underwent AVS and dexamethasone-suppression NP-59 scintigraphy were included between 2010 and 2017. The correlation value between AVS and dexamethasone-suppression NP-59 scintigraphy was assessed using each lateralisation index (LIAVS and LI1NP-59). Tumour presence and size were evaluated using computed tomography. The sensitivity and specificity of dexamethasone-suppression NP-59 scintigraphy for APA according to each lateralisation index threshold were calculated.

Results: Of 29 patients, 12 presented with APA and 17 with BHA according to AVS. The correlation value between LIAVS and LI1NP-59 was 0.63 (P < 0.001). If the cut-off points were 2.55 and 1.80 in all cases, the sensitivity and specificity were 0.33 and 1.00 as well as 0.58 and 0.94, respectively. In adrenal microtumours (maximum diameter ≤10 mm), no cases revealed a cut-off point of >1.8. However, in adrenal macrotumours (maximum diameter >10 mm), the cut-off point of 2.55 represented the best compromise (sensitivity: 0.44; specificity: 1.00).

Conclusion: NP-59 scintigraphy can be used as an alternative to AVS if there is a strong lateralisation on NP-59 scintigraphy and adrenal macrotumours observed on the computed tomography when AVS is technically challenging, particularly in the right adrenal vein cannulation, and if contraindications, such as allergy to contrast materials and renal failure, are observed.
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http://dx.doi.org/10.1097/MNM.0000000000001293DOI Listing
December 2020

Small intestinal bacterial overgrowth as a cause of protracted wound healing and vitamin D deficiency in a spinal cord injured patient with a sacral pressure sore: a case report.

BMC Gastroenterol 2020 Aug 24;20(1):283. Epub 2020 Aug 24.

Department of Molecular Diagnosis, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8670, Japan.

Background: Pressure sores are sometimes refractory to treatment, often due to malnutrition. Small intestinal bacterial overgrowth (SIBO) obstructs absorption in the digestive tract and causes malnutrition. However, little is known about the association between pressure sore wound healing and SIBO. Here, we report a case of a patient with a refractory sacral pressure sore and SIBO.

Case Presentation: A 66-year-old woman who was spinal cord injured 14 years before visiting our hospital presented with the chief complaint of a sacral pressure sore, 10.0 × 6.5 cm in size, which was refractory to treatment. Physical examination showed abdominal distension and emaciation, with a body mass index of 15. Further examination revealed elevated serum alkaline phosphatase (1260 U/L), bilateral tibial fracture, multiple rib fracture, and osteoporosis. We diagnosed the patient with osteomalacia with vitamin D deficiency. Despite oral supplementation, serum levels of calcium, phosphorous, and vitamin D remained low. Also, despite concentrative wound therapy for the sacral pressure sore by plastic surgeons, no wound healing was achieved. Due to a suspicion of disturbances in nutrient absorption, we performed bacterial examination of collected gastric and duodenal fluid, which showed high numbers of bacteria in gastric content (10 E. coli, 10 Streptococcus species, and 10 Neisseria species) and duodenal content (10 E. coli, 10 Candida glabrata). Therefore, we diagnosed the patient with SIBO and started selective decontamination of the digestive tract using polymyxin B sulfate and amphotericin B. After starting treatment for SIBO, the sacral pressure sore began to heal and was nearly healed after 285 days. The patient's serum levels of calcium, phosphorous, vitamin D, and other fat-soluble vitamins also gradually increased after starting treatment for SIBO.

Conclusion: We report a case of a patient with a refractory sacral pressure sore that healed after starting treatment for SIBO. We conclude that SIBO may be an overlooked cause of malnutrition and poor wound healing in patients with chronic pressure sores.
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http://dx.doi.org/10.1186/s12876-020-01423-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444194PMC
August 2020

Interfacial Superconductivity in FeSe Ultrathin Films on SrTiO_{3} Probed by In Situ Independently Driven Four-Point-Probe Measurements.

Phys Rev Lett 2020 Jun;124(22):227002

Department of Physics, Tokyo Institute of Technology, Tokyo 152-8551, Japan.

We investigated the superconducting transport properties of the one-unit-cell FeSe ultrathin films epitaxially grown on undoped SrTiO_{3}(001) (STO) with a well-defined surface structure by in situ independently-driven four-point-probe measurements. Our results unambiguously revealed the detection of the two-dimensional electrical conduction of the films without parallel conduction through the underlying substrate, both in the normal and superconducting states. The monolayer film exhibited a superconducting transition at an onset temperature of 40 K. Surprisingly, the onset of superconductivity was constantly observed at 40 K even for three- and five-unit-cell-thick FeSe films, even though the normal resistivity decreased with increasing thickness. These results agree with the picture of the interfacial superconductivity, where only the FeSe/STO interface and/or the adjacent first layer of FeSe becomes superconducting while the upper layers stay in the normal metallic state. The observed T_{c} is much lower than that reported by a previous in situ transport measurement for FeSe/Nb:STO but consistent with the results obtained by ex situ measurements for FeSe-undoped STO with a capping layer. This suggests that the capping layer is not an essential factor to limit T_{c}. We rather propose that the charge transfer from the doped substrate has a key role to achieve the higher temperature superconductivity in the one-unit-cell FeSe.
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http://dx.doi.org/10.1103/PhysRevLett.124.227002DOI Listing
June 2020

A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing's syndrome other than Cushing's disease.

Endocr J 2020 Aug 1;67(8):841-852. Epub 2020 May 1.

Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto 612-8555/Advanced Medical Care Center, Kusatsu General Hospital, Kusatsu 525-8585, Japan.

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11β-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable.
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http://dx.doi.org/10.1507/endocrj.EJ19-0617DOI Listing
August 2020

Fracture Risk Assessment Tool May Not Indicate Bone Fragility in Women With Type 2 Diabetes.

Am J Med Sci 2020 11 11;360(5):552-559. Epub 2020 Apr 11.

Center for Diabetes, Endocrinology, and Metabolism, Toho University Sakura Medical Center, Chiba, Japan. Electronic address:

Background: Diabetes carries a known risk of bone fracture despite high bone mineral density (BMD). The fracture risk assessment tool (FRAX) predicts the 10-year major osteoporotic fracture risk and hip fracture risk. We investigated the effects of clinical parameters on the FRAX score and evaluated the validity of FRAX for evaluating current bone fragility in diabetes subjects.

Materials And Methods: Forty-seven thousand, three hundred eighty-nine Japanese women participated in the Chiba bone survey, a population-based, multicenter, cross-sectional study of postmenopausal osteoporosis; we estimated FRAX scores without BMD and compared scores between subjects with and without type 2 diabetes.

Results: Mean FRAX major osteoporotic fracture risk was significantly higher in the diabetes group. A multiple regression model demonstrated some clinical parameters that affected the FRAX score and, after adjusting for such parameters, the FRAX score was not significantly different between the diabetes and nondiabetes groups, although the type 2 diabetes rate was significantly higher in subjects with a fracture in the past 5 years, which reflected current bone fragility. After adjusting for clinical parameters, the diabetes rate remained significantly higher in subjects with a fracture in the past 5 years, confirming that type 2 diabetes influences current bone fragility. Our study demonstrated that type 2 diabetes truly carries a risk of bone fracture, but adjusted FRAX major osteoporotic fracture risk is not significantly different between subjects with and without type 2 diabetes.

Conclusions: The FRAX major osteoporotic fracture risk without BMD does not correctly indicate current bone fragility in Japanese middle-aged women with type 2 diabetes.
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http://dx.doi.org/10.1016/j.amjms.2020.04.002DOI Listing
November 2020

Monoamine oxidase B rs1799836 G allele polymorphism is a risk factor for early development of levodopa-induced dyskinesia in Parkinson's disease.

eNeurologicalSci 2020 Jun 6;19:100239. Epub 2020 Apr 6.

Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan.

Background: Dopamine replacement therapy is an established treatment for motor symptoms of Parkinson's disease, but its long-term use is often limited by the eventual development of motor complications, including levodopa-induced dyskinesia. Genetic background, particularly polymorphisms of dopamine metabolism genes, may affect the occurrence of dyskinesia in Parkinson's disease patients.

Methods: We investigated polymorphisms of dopamine metabolism genes, including catechol--methyltransferase, monoamine oxidase B, dopamine beta-hydroxylasedopamine, dopamine receptors D1, D2, and D3, and dopamine transporter, in 110 patients with Parkinson's disease. Cox proportional hazards regression was used to detect associations between genotypes and levodopa-induced dyskinesia.

Results: Monoamine oxidase B rs1799836 was the only polymorphism correlated with risk of dyskinesia. Patients with an AG or GG genotype were more likely to have dyskinesia than those with an AA genotype (adjusted hazard ratio, 3.41; 95% confidence interval, 1.28-9.10). Also, Kaplan-Meier curves demonstrated that patients with an AG or GG genotype developed dyskinesia earlier than those with an AA genotype (log-rank test,  = .004).

Conclusions: In Parkinson's disease patients, the monoamine oxidase B rs1799836 G allele is associated with a greater likelihood of developing dyskinesia than the A allele, possibly due to its association with lower monoamine oxidase B activity in the brain. Thus, detection of monoamine oxidase B polymorphisms may be useful for determining the optimal dosing of antiparkinson medications.
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http://dx.doi.org/10.1016/j.ensci.2020.100239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183157PMC
June 2020

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer.

Oncogenesis 2020 Feb 18;9(2):26. Epub 2020 Feb 18.

Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics, Chiba University Hospital, Chiba, Japan.

Brahma-related gene 1 (BRG1), an ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex controls multipotent neural crest formation by regulating epithelial-mesenchymal transition (EMT)-related genes with adenosine triphosphate-dependent chromodomain-helicase DNA-binding protein 7 (CHD7). The expression of BRG1 engages in pre-mRNA splicing through interacting RNPs in cancers; however, the detailed molecular pathology of how BRG1and CHD7 relate to cancer development remains largely unveiled. This study demonstrated novel post-transcriptional regulation of BRG1 in EMT and relationship with FIRΔexon2, which is a splicing variant of the far-upstream element-binding protein (FUBP) 1-interacting repressor (FIR) lacking exon 2, which fails to repress c-myc transcription in cancers. Previously, we have reported that FIR complete knockout mice (FIR) was embryonic lethal before E9.5, suggesting FIR is crucial for development. FIRΔexon2 acetylated H3K27 on promoter of BRG1 by CHIP-sequence and suppressed BRG1 expression post-transcriptionally; herein BRG1 suppressed Snai1 that is a transcriptional suppressor of E-cadherin that prevents cancer invasion and metastasis. Ribosomal proteins, hnRNPs, splicing-related factors, poly (A) binding proteins, mRNA-binding proteins, tRNA, DEAD box, and WD-repeat proteins were identified as co-immunoprecipitated proteins with FIR and FIRΔexon2 by redoing exhaustive mass spectrometry analysis. Furthermore, the effect of FIRΔexon2 on FGF8 mRNA splicing was examined as an indicator of neural development due to impaired CHD7 revealed in CHARGE syndrome. Expectedly, siRNA of FIRΔexon2 altered FGF8 pre-mRNA splicing, indicated close molecular interaction among FIRΔexon2, BRG1 and CHD7. FIRΔexon2 mRNA was elevated in human gastric cancers but not in non-invasive gastric tumors in FIR mice (K19-Wnt1/C2mE x FIR). The levels of FIR family (FIR, FIRΔexon2 and PUF60), BRG1, Snai1, FBW7, E-cadherin, c-Myc, cyclin-E, and SAP155 increased in the gastric tumors in FIR mice compared to those expressed in wild-type mice. FIR family, Snai1, cyclin-E, BRG1, and c-Myc showed trends toward higher expression in larger tumors than in smaller tumors in Gan-mice (K19-Wnt1/C2mE). The expressions of BRG1 and Snai1 were positively correlated in the gastric tumors of the Gan-mice. Finally, BRG1 is a candidate substrate of F-box and WD-repeat domain-containing 7 (FBW7) revealed by three-dimensional crystal structure analysis that the U2AF-homology motif (UHM) of FIRΔexon2 interacted with tryptophan-425 and asparate-399 (WD)-like motif in the degron pocket of FBW7 as a UHM-ligand motif. Together, FIRΔexon2 engages in multi-step post-transcriptional regulation of BRG1, affecting EMT through the BRG1/Snai1/E-cadherin pathway and promoting tumor proliferation and invasion of gastric cancers.
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http://dx.doi.org/10.1038/s41389-020-0205-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028737PMC
February 2020

A simple method for sequencing the whole human mitochondrial genome directly from samples and its application to genetic testing.

Sci Rep 2019 11 22;9(1):17411. Epub 2019 Nov 22.

Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Next-generation sequencing (NGS) is a revolutionary sequencing technology for analyzing genomes. However, preprocessing methods for mitochondrial DNA (mtDNA) sequencing remain complex, and it is required to develop an authenticated preprocessing method. Here, we developed a simple and easy preprocessing method based on isothermal rolling circle mtDNA amplification using commercially available reagents. Isothermal amplification of mtDNA was successfully performed using both nanoliter quantities of plasma directly and 25 ng of total DNA extracted from blood or tissue samples. Prior to mtDNA amplification, it was necessary to treat the extracted total DNA with Exonuclease V, but it was not required to treat plasma. The NGS libraries generated from the amplified mtDNA provided sequencing coverage of the entire human mitochondrial genome. Furthermore, the sequencing results successfully detected heteroplasmy in patient samples, with called mutations and variants matching those from previous, independent, Sanger sequencing analysis. Additionally, a novel single nucleotide variant was detected in a healthy volunteer. The successful analysis of mtDNA using very small samples from patients is likely to be valuable in clinical medicine, as it could reduce patient discomfort by reducing sampling-associated damage to tissues. Overall, the simple and convenient preprocessing method described herein may facilitate the future development of NGS-based clinical and forensic mtDNA tests.
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http://dx.doi.org/10.1038/s41598-019-53449-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874554PMC
November 2019

Cell type-specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells.

J Exp Med 2020 01;217(1)

Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA.

The zinc finger transcription factor, Bcl11b, is expressed in T cells and group 2 innate lymphoid cells (ILC2s) among hematopoietic cells. In early T-lineage cells, Bcl11b directly binds and represses the gene encoding the E protein antagonist, Id2, preventing pro-T cells from adopting innate-like fates. In contrast, ILC2s co-express both Bcl11b and Id2. To address this contradiction, we have directly compared Bcl11b action mechanisms in pro-T cells and ILC2s. We found that Bcl11b binding to regions across the genome shows distinct cell type-specific motif preferences. Bcl11b occupies functionally different sites in lineage-specific patterns and controls totally different sets of target genes in these cell types. In addition, Bcl11b bears cell type-specific post-translational modifications and organizes different cell type-specific protein complexes. However, both cell types use the same distal enhancer region to control timing of Bcl11b activation. Therefore, although pro-T cells and ILC2s both need Bcl11b for optimal development and function, Bcl11b works substantially differently in these two cell types.
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http://dx.doi.org/10.1084/jem.20190972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037248PMC
January 2020

Aldosterone Reduction Rate After Saline Infusion Test May Be a Novel Prediction in Patients With Primary Aldosteronism.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.

Objective: Accurate assessment and localization of aldosterone-producing adenomas (APAs) are essential for the treatment of primary aldosteronism (PA). Although adrenal venous sampling (AVS) is the standard method of reference for subtype diagnosis in PA, controversy exists concerning the criteria for its interpretation. This study aims to determine better indicators that can reliably predict subtypes of PA.

Method: Retrospective, single-cohort analysis including 209 patients with PA who were subjected to AVS. Eighty-two patients whose plasma aldosterone concentrations (PAC) were normalized after surgery were histopathologically or genetically diagnosed with APA. The accuracy of image findings was compared to AVS results. Receiver operating characteristic (ROC) curve analysis between the operated and the no-apparent laterality groups was performed using AVS parameters and loading test for diagnosis of PA.

Result: Agreement between image findings and AVS results was 56.3%. ROC curve analysis revealed that the lateralization index (LI) after adrenocorticotropin stimulation cutoff was 2.40, with 98.8% sensitivity and 97.1% specificity. The contralateral suppression index (CSI) cutoff value was 1.19, with 98.0% sensitivity and 93.9% specificity. All patients over the LI and CSI cutoff values exhibited unilateral subtypes. Among the loading test, the best classification accuracy was achieved using the PAC reduction rate after a saline infusion test (SIT) >33.8%, which yielded 87.2% sensitivity or a PAC after a SIT <87.9 pg/mL with 86.2% specificity for predicting bilateral PA.

Conclusion: The combined criteria of the PAC reduction rate and PAC after the SIT can determine which subset of patients with APA who should be performed AVS for validation.
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http://dx.doi.org/10.1210/clinem/dgz092DOI Listing
March 2020

A Case of Hashimoto's Thyroiditis with Multiple Drug Resistance and High Expression of Efflux Transporters.

J Clin Endocrinol Metab 2020 02;105(2)

Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.

Context: Hashimoto's thyroiditis is the most common cause of hypothyroidism. Patients usually respond well to oral synthetic thyroxine (levothyroxine); however, for unknown reasons some individuals present with treatment-resistant Hashimoto thyroiditis. In cases of cancer and certain infectious diseases, the ATP binding cassette (ABC) transporters have been implicated in multidrug resistance, and we hypothesized and investigated a role of ABC transporters in drug-resistant Hashimoto's thyroiditis.

Case Description: The patient whose case we report had a history of Hashimoto's thyroiditis, immune thrombocytopenia, and refractory hypertension, with varying treatment resistance to the oral medications prescribed for each condition. In order to establish or exclude a genetic basis for her illness, we examined the patient's gene expression profiles using peripheral blood leukocytes, and found that ABCG2/BCRPexpression was significantly high compared with healthy volunteers. Also, the increased daunomycin efflux capacity of our patient's lymphocytes was successfully inhibited by fumitremorgin C, a specific ABCG2/BCRP inhibitor, and the patient's level of thyroid-stimulating hormone increased by 248.6% after administration of intact levothyroxine tablets but decreased by 45.1% when tablets were crushed. Her average blood pressure decreased from 166.3/108.5 mmHg to 125.9/78.8 mmHg when switching from intact to crushed losartan tablets.

Conclusions: High expression and accelerated efflux transporter activity of ABCG2/BCRP in the small intestine are expected to contribute to the ineffectiveness of orally administered intact tablets in cases with treatment-resistant Hashimoto's thyroiditis, and crushed tablets can be more effective for some of these patients.
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http://dx.doi.org/10.1210/clinem/dgz073DOI Listing
February 2020

Editorial Comment from Dr Tanaka to Tadalafil is sufficiently effective for severe chronic prostatitis/chronic pelvic pain syndrome in patients with benign prostatic hyperplasia.

Authors:
Tomoaki Tanaka

Int J Urol 2020 01 10;27(1):58-59. Epub 2019 Oct 10.

Department of Urology, Suita Municipal Hospital, Suita, Osaka, Japan.

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http://dx.doi.org/10.1111/iju.14134DOI Listing
January 2020

Latest insights on ABO-incompatible living-donor renal transplantation.

Int J Urol 2020 Jan 14;27(1):30-38. Epub 2019 Sep 14.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

This review summarizes the latest insights on ABO-incompatible living-donor renal transplantation. Desensitization protocols and clinical outcomes were investigated, and a comparison was made with kidney-paired donation, which is not permitted in Japan for ethical reasons. Although renal transplantation is greatly beneficial for most patients with end-stage kidney disease, many of these patients must remain on dialysis therapy for extended periods due to the scarcity of organs from deceased donors. ABO blood type incompatibility was once believed to be a contraindication to renal transplantation due to the increased risk for antibody-mediated rejection and early graft loss attributable to isoagglutinins. Recently, pretransplant desensitization strategies, such as removal of isoagglutinins and antibody-producing cells, have achieved successful outcomes, although it remains unclear whether graft survival and patient morbidity are equivalent to those for ABO-compatible renal transplantation. The present review suggested that ABO-incompatible living-donor renal transplantation might be a favorable radical renal replacement therapy for patients with end-stage kidney disease.
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http://dx.doi.org/10.1111/iju.14109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004137PMC
January 2020

Correlation between urinary fractionated metanephrines in 24-hour and spot urine samples for evaluating the therapeutic effect of metyrosine: a subanalysis of a multicenter, open-label phase I/II study.

Endocr J 2019 Dec 10;66(12):1063-1072. Epub 2019 Sep 10.

Clinical Research Institute for Endocrinology and Metabolic Diseases, National Hospital Organization Kyoto Medical Center, Kyoto 612-8555, Japan.

We recently conducted an open-label phase I/II study to evaluate the efficacy and safety of preoperative and chronic treatment with metyrosine (an inhibitor of catecholamine synthesis) in pheochromocytoma/paraganglioma (PPGL) in Japan. We compared creatinine-corrected metanephrine fractions in spot urine and 24-hour urine samples (the current standard for the screening and diagnosis of PPGLs) from 16 patients to assess the therapeutic effect of metyrosine. Percent changes from baseline in urinary metanephrine (uMN) or normetanephrine (uNMN) were compared between spot and 24-hour urine samples. Mean percent changes in uMN or uNMN in spot and 24-hour urine were -26.36% and -29.27%, respectively. The difference in the percent change from baseline between uMN or uNMN in spot and 24-hour urine was small (-2.90%). The correlation coefficient was 0.87 for percent changes from baseline between uMN or uNMN measured in spot and 24-hour urine. The area under the receiver operator characteristic (ROC) curve of uMN or uNMN measured in spot urine vs. 24-hour urine (reference standard) to assess the efficacy of metyrosine treatment was 0.93. Correlations and ROCs between 24-hour urinary vanillylmandelic acid, adrenaline, and noradrenaline and 24-hour uMN or uNMN were similar to those between spot uMN or uNMN and 24-hour uMN or uNMN. No large difference was observed between spot and 24-hour urine for the assessment of metyrosine treatment by quantifying uMN or uNMN in Japanese patients with PPGLs. These results suggest that spot urine samples may be useful in assessing the therapeutic effect of metyrosine.
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http://dx.doi.org/10.1507/endocrj.EJ19-0125DOI Listing
December 2019

Characteristics of urodynamic study parameters associated with intermediate-term continence after robot-assisted radical prostatectomy in elderly patients.

Aging Male 2020 Dec 30;23(5):1039-1045. Epub 2019 Aug 30.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Osaka, Japan.

Purpose: To investigate the relationship between urodynamic study (UDS) data and recovery of urinary incontinence (UI) in elderly patients who underwent robot-assisted radical prostatectomy (RARP).

Materials And Methods: Seventy-five prostate cancer (PCa) patients received UDS before and at 3 months after RARP. They were divided into two groups; a younger group (<70 years old,  = 47) and older group (≥70 years,  = 28), and each was classified according to urinary continence (UC) or UI at 3 months post-RARP. Continence was defined as being pad-free or 1-safety pad usage per day.

Results: In the older group, preoperative maximum urethral closure pressure (MUCP) in the UI group was significantly lower than that in the UC group. Detrusor overactivity (DO) rate was significantly higher in the older UI group than in the older UC group at both pre- and 3 months post-RARP. Persistent DO rate pre- and post-RARP was significantly higher in the older group than in the younger group. Regardless of age, postoperative DO was an independent predictor of UI 6 months post-RARP.

Conclusions: In elderly patients, low preoperative MUCP and both pre- and postoperative DO are associated with postoperative UI.
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http://dx.doi.org/10.1080/13685538.2019.1659767DOI Listing
December 2020

Adipose-Derived Stem Cells and Ceiling Culture-Derived Preadipocytes Cultured from Subcutaneous Fat Tissue Differ in Their Epigenetic Characteristics and Osteogenic Potential.

Plast Reconstr Surg 2019 09;144(3):644-655

From the Departments of Plastic Surgery and Molecular Diagnosis and the Center for Advanced Medicine, Chiba University; the Department of General Surgery, National Organization Hospital Mito Medical Center; and the Department of Research and Development, Toho University.

Background: Adipose-derived stem cells and ceiling culture-derived preadipocytes can be harvested from subcutaneous adipose tissue. Little is known about the epigenetic differences, which may contribute to differences in osteogenic potential, between these cell types. The purpose of this study was to address the osteogenic potential and underlying epigenetic status of adipose-derived stem cells and ceiling culture-derived preadipocytes.

Methods: Adipose-derived stem cells and ceiling culture-derived preadipocytes were cultured from abdominal subcutaneous fat tissues of four metabolically healthy, lean female patients. After 7 weeks of culture, cellular responses to osteogenic differentiation media were examined. To evaluate the osteogenic potentials of undifferentiated adipose-derived stem cells and ceiling culture-derived preadipocytes, two types of epigenetic assessment were performed using next-generation sequencing: DNA methylation assays with the Human Methylation 450K BeadChip, and chromatin immunoprecipitation assays for trimethylation of histone H3 at lysine 4.

Results: Human ceiling culture-derived preadipocytes showed greater osteogenic differentiation ability than did adipose-derived stem cells. In an epigenetic survey of the promoters of four osteogenic regulator genes (RUNX2, SP7, ATF4, and BGLAP), the authors found a general trend toward decreased CpG methylation and increased trimethylation of histone H3 at lysine 4 levels in ceiling culture-derived preadipocytes as compared to adipose-derived stem cells, indicating that these genes were more likely to be highly expressed in ceiling culture-derived preadipocytes.

Conclusions: The surveyed epigenetic differences between adipose-derived stem cells and ceiling culture-derived preadipocytes were consistent with the observed differences in osteogenic potential. These results enhance the authors' understanding of these cells and will facilitate their further application in regenerative medicine.
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http://dx.doi.org/10.1097/PRS.0000000000005913DOI Listing
September 2019

A Multiplatform Inversion Estimation of Statewide and Regional Methane Emissions in California during 2014-2016.

Environ Sci Technol 2019 Aug 2;53(16):9636-9645. Epub 2019 Aug 2.

California Air Resources Board , 1001 I Street , Sacramento , California 95814 , United States.

California methane (CH) emissions are quantified for three years from two tower networks and one aircraft campaign. We used backward trajectory simulations and a mesoscale Bayesian inverse model, initialized by three inventories, to achieve the emission quantification. Results show total statewide CH emissions of 2.05 ± 0.26 (at 95% confidence) Tg/yr, which is 1.14 to 1.47 times greater than the anthropogenic emission estimates by California Air Resource Board (CARB). Some of differences could be biogenic emissions, superemitter point sources, and other episodic emissions which may not be completely included in the CARB inventory. San Joaquin Valley (SJV) has the largest CH emissions (0.94 ± 0.18 Tg/yr), followed by the South Coast Air Basin, the Sacramento Valley, and the San Francisco Bay Area at 0.39 ± 0.18, 0.21 ± 0.04, and 0.16 ± 0.05 Tg/yr, respectively. The dairy and oil/gas production sources in the SJV contribute 0.44 ± 0.36 and 0.22 ± 0.23 Tg CH/yr, respectively. This study has important policy implications for regulatory programs, as it provides a thorough multiyear evaluation of the emissions inventory using independent atmospheric measurements and investigates the utility of a complementary multiplatform approach in understanding the spatial and temporal patterns of CH emissions in the state and identifies opportunities for the expansion and applications of the monitoring network.
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http://dx.doi.org/10.1021/acs.est.9b01769DOI Listing
August 2019

Fatty acid desaturase 2 is up-regulated by the treatment with statin through geranylgeranyl pyrophosphate-dependent Rho kinase pathway in HepG2 cells.

Sci Rep 2019 07 10;9(1):10009. Epub 2019 Jul 10.

Center for Diabetes, Metabolism and Endocrinology, Toho University Sakura Medical Center, Sakura, Japan.

Statins have been reported to increase the plasma concentration of arachidonic acid (AA), an omega-6 long chain polyunsaturated fatty acid (LCPUFA) in several clinical studies indicating that statins affect the endogenous synthesis of LCUFAs. In the present study, we investigated the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in LCPUFA synthesis, especially focusing on fatty acid desaturases (Fads) 2, using the human hepatocellular carcinoma cell line HepG2. Cell number and the activity of caspase-3 and 7 (caspase-3/7) was measured using a commercial kit. Gene expression was analyzed by quantitative real-time PCR. Protein expression was detected by Western blot analysis. Atorvastatin decreased cell viability and increased caspase-3/7 activity in a dose-dependent manner. At lower concentrations, atorvastatin stimulated both mRNA and protein expression of Fads2, and increased mRNA expression of FADS1 and ELVOL5. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), but not cholesterol, fully reversed atorvastatin-induced upregulation of Fads2, and mevalonate-effected reversal was inhibited by treatment with the Rho-associated protein kinase inhibitor Y-27632. These data clearly demonstrated that in human HepG2 cells, statins affect the endogenous synthesis of LCPUFAs by regulation of not only Fads2, but also Fads1 and Elovl5, through the GGPP-dependent Rho kinase pathway.
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http://dx.doi.org/10.1038/s41598-019-46461-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620338PMC
July 2019

Transcriptome analysis revealed bisphenol A and nonylphenol affect reproduction.

Reprod Toxicol 2019 09 6;88:39-47. Epub 2019 Jul 6.

Laboratory of Cell Engineering, Department of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan. Electronic address:

Effects of endocrine disrupting chemicals (EDCs) on reproduction have not been fully explained comprehensively. In this study, we tried to validate the common effect of Bisphenol A (BPA) and Nonylphenol (NP) on the differentiation of embryonic stem (ES) cells and found that they modify the expression of germ cell specific genes. To elucidate functional significance on biological process, we performed Gene Ontology (GO)-based microarray analysis comparing with published GeneChip data of primordial germ cell development in vivo. Cluster analysis of gene expression profile revealed that EDC treatment and primordial germ cell (PGC) development shared characteristic cluster consists of GO terms related to "germ cell development" and "reproduction". In the GO term "reproduction", meiosis related genes showed high expression level by EDC exposure. These results suggest that BPA and NP affect not only some of the germ cell specific genes, but functionally interferes germ cell development and reproduction.
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http://dx.doi.org/10.1016/j.reprotox.2019.06.006DOI Listing
September 2019
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